IUPHAR/BPS Guide to Pharmacology CITE

5-Hydroxytryptamine receptors in GtoPdb v.2023.1

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5-HT receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on 5-HT receptors [198] and subsequently revised [180]) are, with the exception of the ionotropic 5-HT₃ class, GPCRs where the endogenous agonist is 5-hydroxytryptamine. The diversity of metabotropic 5-HT receptors is increased by alternative splicing that produces isoforms of the 5-HT_2A (non-functional), 5-HT_2C (non-functional), 5-HT₄, 5-HT₆ (non-functional) and 5-HT₇ receptors. Unique amongst the GPCRs, RNA editing produces 5-HT_2C receptor isoforms that differ in function, such as efficiency and specificity of coupling to G_q/11 and also pharmacology [40, 491]. Most 5-HT receptors (except 5-ht_1e and 5-ht_5b) play specific roles mediating functional responses in different tissues (reviewed by [471, 387]).

Acetylcholine receptors (muscarinic) in GtoPdb v.2023.1

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Muscarinic acetylcholine receptors (mAChRs) (nomenclature as agreed by the NC-IUPHAR Subcommittee on Muscarinic Acetylcholine Receptors [53]) are activated by the endogenous agonist acetylcholine. All five (M1-M5) mAChRs are ubiquitously expressed in the human body and are therefore attractive targets for many disorders. Functionally, M₁, M₃, and M₅ mAChRs preferentially couple to G_q/11 proteins, whilst M₂ and M₄ mAChRs predominantly couple to G_i/o proteins. Both agonists and antagonists of mAChRs are clinically approved drugs, including pilocarpine for the treatment of elevated intra-ocular pressure and glaucoma, and atropine for the treatment of bradycardia and poisoning by muscarinic agents such as organophosphates. Of note, it has been observed that mAChRs dimerise reversibly [134] and that dimerisation/oligomerisation can be affected by ligands [183, 196].

Adenosine receptors in GtoPdb v.2023.1

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Adenosine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adenosine Receptors [112]) are activated by the endogenous ligand adenosine (potentially inosine also at A₃ receptors). Crystal structures for the antagonist-bound [155, 316, 224, 62], agonist-bound [379, 205, 206] and G protein-bound A_2A adenosine receptors [49] have been described. The structures of an antagonist-bound A₁ receptor [130] and an adenosine-bound A₁ receptor-G_i complex [87] have been resolved by cryo-electronmicroscopy. Another structure of an antagonist-bound A₁ receptor obtained with X-ray crystallography has also been reported [58]. The structure of the A_2B receptor has also been elucidated [57]. caffeine is a nonselective antagonist for adenosine receptors, while istradefylline, a selective A_2A receptor antagonist, is on the market for the treatment of Parkinson's disease.

Adrenoceptors in GtoPdb v.2023.1

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The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [64, 194].

Adrenoceptors, α₁
The three α₁-adrenoceptor subtypes α_1A, α_1B and α_1D are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. -(-)phenylephrine, methoxamine and cirazoline are agonists and prazosin and doxazosin antagonists considered selective for α₁- relative to α₂-adrenoceptors. [³H]prazosin and [¹²⁵I]HEAT (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca²⁺ channels. Fluorescent derivatives of prazosin (Bodipy FLprazosin- QAPB) are used to examine cellular localisation of α₁-adrenoceptors. α₁-Adrenoceptor agonists are used as nasal decongestants; antagonists to treat symptoms of benign prostatic hyperplasia (alfuzosin, doxazosin, terazosin, tamsulosin and silodosin, with the last two compounds being α1_A-adrenoceptor selective and claiming to relax bladder neck tone with less hypotension); and to a lesser extent hypertension (doxazosin, terazosin). The α₁- and β₂-adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of α₁-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are α₁-adrenoceptor antagonists contributing to side effects such as orthostatic hypotension.

Adrenoceptors, α₂
The three α₂-adrenoceptor subtypes α_2A, α_2B and α_2C are activated by (-)-adrenaline and with lower potency by (-)-noradrenaline. brimonidine and talipexole are agonists and rauwolscine and yohimbine antagonists selective for α₂- relative to α₁-adrenoceptors. [³H]rauwolscine, [³H]brimonidine and [³H]RX821002 are relatively selective radioligands. There are species variations in the pharmacology of the α_2A-adrenoceptor. Multiple mutations of α₂-adrenoceptors have been described, some associated with alterations in function. Presynaptic α₂-adrenoceptors regulate many functions in the nervous system. The α₂-adrenoceptor agonists clonidine, guanabenz and brimonidine affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. clonidine is an anti-hypertensive (relatively little used) and counteracts opioid withdrawal. dexmedetomidine (also xylazine) is increasingly used as a sedative and analgesic in human [33] and veterinary medicine and has sympatholytic and anxiolytic properties. The α₂-adrenoceptor antagonist mirtazapine is used as an anti-depressant. The α_2B subtype appears to be involved in neurotransmission in the spinal cord and α_2C in regulating catecholamine release from adrenal chromaffin cells. Although subtype-selective antagonists have been developed, none are used clinically and they remain experimental tools.

Adrenoceptors, β
The three β-adrenoceptor subtypes β₁, β₂ and β₃ are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is selective for β-adrenoceptors relative to α₁- and α₂-adrenoceptors, while propranolol (pK_i 8.2-9.2) and cyanopindolol (pK_i 10.0-11.0) are relatively selective antagonists for β₁- and β₂- relative to β₃-adrenoceptors. (-)-noradrenaline, xamoterol and (-)-Ro 363 show selectivity for β₁- relative to β₂-adrenoceptors. Pharmacological differences exist between human and mouse β₃-adrenoceptors, and the 'rodent selective' agonists BRL 37344 and CL316243 have low efficacy at the human β₃-adrenoceptor whereas CGP 12177 (low potency) and L 755507 activate human β₃-adrenoceptors [88]. β₃-Adrenoceptors are resistant to blockade by propranolol, but can be blocked by high concentrations of bupranolol. SR59230A has reasonably high affinity at β₃-adrenoceptors, but does not discriminate between the three β- subtypes [332] whereas L-748337 is more selective. [¹²⁵I]-cyanopindolol, [¹²⁵I]-hydroxy benzylpindolol and [³H]-alprenolol are high affinity radioligands that label β₁- and β₂- adrenoceptors and β₃-adrenoceptors can be labelled with higher concentrations (nM) of [¹²⁵I]-cyanopindolol together with β₁- and β₂-adrenoceptor antagonists. Fluorescent ligands such as BODIPY-TMR-CGP12177 can be used to track β-adrenoceptors at the cellular level [8]. Somewhat selective β₁-adrenoceptor agonists (denopamine, dobutamine) are used short term to treat cardiogenic shock but, chronically, reduce survival. β₁-Adrenoceptor-preferring antagonists are used to treat cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol) but also in combination with other treatments to treat hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol) [528]. Cardiac failure is also treated with carvedilol that blocks β₁- and β₂-adrenoceptors, as well as α₁-adrenoceptors. Short (salbutamol, terbutaline) and long (formoterol, salmeterol) acting β₂-adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generation β-adrenoceptor antagonists (propranolol) block both β₁- and β₂-adrenoceptors and there are no β₂-adrenoceptor-selective antagonists used therapeutically. The β₃-adrenoceptor agonist mirabegron is used to control overactive bladder syndrome. There is evidence to suggest that β-adrenoceptor antagonists can reduce metastasis in certain types of cancer [197].

Complement peptide receptors in GtoPdb v.2023.1

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Complement peptide receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Complement peptide receptors [113]) are activated by the endogenous ~75 amino-acid anaphylatoxin polypeptides C3a and C5a, generated upon stimulation of the complement cascade. C3a and C5a exert their functions through binding to their receptors (C3a receptor, C5a receptor 1 and C5a receptor 2), causing cell recruitment and triggering cellular degranulation that contributes to local inflammation.

Angiotensin receptors in GtoPdb v.2023.1

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The actions of angiotensin II (Ang II) are mediated by AT₁ and AT₂ receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Angiotensin receptors [63, 155]), which have around 30% sequence similarity. The decapeptide angiotensin I, the octapeptide angiotensin II and the heptapeptide angiotensin III are endogenous ligands. losartan, candesartan, olmesartan, telmisartan, etc. are clinically used AT₁ receptor blockers.

Apelin receptor in GtoPdb v.2023.1

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The apelin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on the apelin receptor [73] and subsequently updated [75]) responds to apelin, a 36 amino-acid peptide derived initially from bovine stomach. apelin-36, apelin-13 and [Pyr¹]apelin-13 are the predominant endogenous ligands which are cleaved from a 77 amino-acid precursor peptide (APLN, Q9ULZ1) [88]. A second family of peptides discovered independently and named Elabela [13] or Toddler, that has little sequence similarity to apelin, is present, and functional at the apelin receptor in the adult cardiovascular system [97, 71]. The enzymatic pathways generating biologically active apelin and Elabela isoforms have not been determined but both propeptides include sites for potential proprotein convertase processing [81]. Structure-activity relationship Elabela analogues have been described [65, 90]. The stoichiometry of apelin receptor-heterotrimeric G protein complexes has been studied using cryogenic-electron microscopy [98].

Bile acid receptor in GtoPdb v.2023.1

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The bile acid receptor (GPBA) responds to bile acids produced during the liver metabolism of cholesterol. Selective agonists are promising drugs for the treatment of metabolic disorders, such as type II diabetes, obesity and atherosclerosis.

Bombesin receptors in GtoPdb v.2023.1

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Mammalian bombesin (Bn) receptors comprise 3 subtypes: BB₁, BB₂, BB₃ (nomenclature recommended by the NC-IUPHAR Subcommittee on bombesin receptors, [117, 4]). BB₁ and BB₂ are activated by the endogenous ligands neuromedin B (NMB), gastrin-releasing peptide (GRP), and GRP-(18-27). bombesin is a tetra-decapeptide, originally derived from amphibians and structurally closely related to GRP. The three Bn receptor subtypes couple primarily to the G_q/11 and G_12/13 family of G proteins [117]. Each of these receptors is widely distributed in the CNS and peripheral tissues [80, 117, 261, 290, 248, 375, 114, 164, 165]. Activation of BB₁ and BB₂ receptors causes a wide range of physiological/pathophysiogical actions, including the stimulation of normal and neoplastic tissue growth, smooth-muscle contraction, respiration, gastrointestinal motility, feeding behavior, secretion and many central nervous system effects including regulation of circadian rhythm, body temperature control, sighing, behavioral disorders and mediation of pruritus [153, 211, 255, 117, 205, 261, 318, 70, 35, 345, 212, 36]. BB₃ is an orphan receptor, although some propose it is constitutively active [330]. BB₃ receptor knockout studies show it has important roles in glucose and insulin regulation, metabolic homeostasis, feeding, regulation of body temperature, obesity, diabetes mellitus and growth of normal/neoplastic tissues [152, 80, 168, 224, 359, 209]. Bn receptors are one of the most frequently overexpressed receptors in cancers and are receiving increased attention for their roles in tumor growth, as well as for tumour imaging and for receptor-targeted cytotoxicity [211, 288, 9, 167, 171, 172, 135, 202]. Bn receptors are also receiving attention because they are one of the primary neurotransmitters for pruritus [36, 127, 35, 318].

Bradykinin receptors in GtoPdb v.2023.1

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Bradykinin (or kinin) receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Bradykinin (kinin) Receptors [92]) are activated by the endogenous peptides bradykinin (BK), [des-Arg⁹]bradykinin, Lys-BK (kallidin), [des-Arg¹⁰]kallidin, [Phospho-Ser⁶]-Bradykinin, T-kinin (Ile-Ser-BK), [Hyp³]bradykinin and Lys-[Hyp³]-bradykinin. Variation in pharmacology and activity of B₁ and B₂ receptor antagonists at species orthologs has been documented. icatibant (Hoe140, Firazir) is approved in North America and Europe for the treatment of acute attacks of hereditary angioedema. Inhibition of bradykinin with icatibant in COVID-19 infection is under clinical evaluation, with trial NCT05407597 expected to complete in mid 2023.

Calcitonin receptors in GtoPdb v.2023.1

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This receptor family comprises a group of receptors for the calcitonin/CGRP family of peptides. The calcitonin (CT), amylin (AMY), calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on CGRP, AM, AMY, and CT receptors [131, 74, 71]) are generated by the genes CALCR (which codes for the CT receptor, CTR) and CALCRL (which codes for the calcitonin receptor-like receptor, CLR, previously known as CRLR). Their function and pharmacology are altered in the presence of RAMPs (receptor activity-modifying proteins), which are single TM domain proteins of ca. 150 amino acids, identified as a family of three members; RAMP1, RAMP2 and RAMP3. There are splice variants of the CTR; these in turn produce variants of AMY receptors [131], some of which can be potently activated by CGRP. The endogenous agonists are the peptides calcitonin, α-CGRP (formerly known as CGRP-I), β-CGRP (formerly known as CGRP-II), amylin (occasionally called islet-amyloid polypeptide, diabetes-associated polypeptide), adrenomedullin and adrenomedullin 2/intermedin. There are species differences in peptide sequences, particularly for the CTs. CTR-stimulating peptide (CRSP) is another member of the family with selectivity for the CTR but it is not expressed in humans [93]. CLR (calcitonin receptor-like receptor) by itself binds no known endogenous ligand, but in the presence of RAMPs it gives receptors for CGRP, adrenomedullin and adrenomedullin 2/intermedin. There are several approved drugs that target this receptor family, such as pramlintide, erenumab, and the "gepant" class of CGRP receptor antagonists. There are also species differences in agonist pharmacology; for example, CGRP displays potent activity at multiple rat and mouse receptors [58, 15]. The summary table only reflects human receptor pharmacology.

Calcium-sensing receptor in GtoPdb v.2023.1

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The calcium-sensing receptor (CaS, provisional nomenclature as recommended by NC-IUPHAR [47] and subsequently updated [77]) responds to multiple endogenous ligands, including extracellular calcium and other divalent/trivalent cations, polyamines and polycationic peptides, L-amino acids (particularly L-Trp and L-Phe), glutathione and various peptide analogues, ionic strength and extracellular pH (reviewed in [78]). While divalent/trivalent cations, polyamines and polycations are CaS receptor agonists [14, 110], L-amino acids, glutamyl peptides, ionic strength and pH are allosteric modulators of agonist function [36, 47, 61, 108, 109]. Indeed, L-amino acids have been identified as "co-agonists", with both concomitant calcium and L-amino acid binding required for full receptor activation [149, 54]. The sensitivity of the CaS receptor to primary agonists is increased by elevated extracellular pH [18] or decreased extracellular ionic strength [109] while sensitivity is decreased by pathophysiological phosphate concentrations [20]. This receptor bears no sequence or structural relation to the plant calcium receptor, also called CaS.

Cannabinoid receptors in GtoPdb v.2023.1

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Cannabinoid receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Cannabinoid Receptors [119]) are activated by endogenous ligands that include N-arachidonoylethanolamine (anandamide), N-homo-γ-linolenoylethanolamine, N-docosatetra-7,10,13,16-enoylethanolamine and 2-arachidonoylglycerol. Potency determinations of endogenous agonists at these receptors are complicated by the possibility of differential susceptibility of endogenous ligands to enzymatic conversion [5].

There are currently three licenced cannabinoid medicines each of which contains a compound that can activate CB₁ and CB₂ receptors [111]. Two of these medicines were developed to suppress nausea and vomiting produced by chemotherapy. These are nabilone (Cesamet®), a synthetic CB₁/CB₂ receptor agonist, and synthetic Δ⁹-tetrahydrocannabinol (Marinol®; dronabinol), which can also be used as an appetite stimulant. The third medicine, Sativex®, contains mainly Δ⁹-tetrahydrocannabinol and cannabidiol, both extracted from cannabis, and is used to treat multiple sclerosis and cancer pain.

Chemokine receptors in GtoPdb v.2023.1

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Chemokine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [438, 437, 32]) comprise a large subfamily of 7TM proteins that bind one or more chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non-hematopoietic roles have been identified for many chemokines in the areas of embryonic development, immune cell proliferation, activation and death, viral infection, and as antibacterials, among others. Chemokine receptors can be divided by function into two main groups: G protein-coupled chemokine receptors, which mediate leukocyte trafficking, and "Atypical chemokine receptors", which may signal through non-G protein-coupled mechanisms and act as chemokine scavengers to downregulate inflammation or shape chemokine gradients [32].

Chemokines in turn can be divided by structure into four subclasses by the number and arrangement of conserved cysteines. CC (also known as β-chemokines; n= 28), CXC (also known as α-chemokines; n= 17) and CX3C (n= 1) chemokines all have four conserved cysteines, with zero, one and three amino acids separating the first two cysteines respectively. C chemokines (n= 2) have only the second and fourth cysteines found in other chemokines. Chemokines can also be classified by function into homeostatic and inflammatory subgroups. Most chemokine receptors are able to bind multiple high-affinity chemokine ligands, but the ligands for a given receptor are almost always restricted to the same structural subclass. Most chemokines bind to more than one receptor subtype. Receptors for inflammatory chemokines are typically highly promiscuous with regard to ligand specificity, and may lack a selective endogenous ligand. G protein-coupled chemokine receptors are named acccording to the class of chemokines bound, whereas ACKR is the root acronym for atypical chemokine receptors [33]. There can be substantial cross-species differences in the sequences of both chemokines and chemokine receptors, and in the pharmacology and biology of chemokine receptors. Endogenous and microbial non-chemokine ligands have also been identified for chemokine receptors. Many chemokine receptors function as HIV co-receptors, but CCR5 is the only one demonstrated to play an essential role in HIV/AIDS pathogenesis. The tables include both standard chemokine receptor names [693] and aliases.

Cholecystokinin receptors in GtoPdb v.2023.1

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Cholecystokinin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on CCK receptors [90]) are activated by the endogenous peptides cholecystokinin-8 (CCK-8), CCK-33, CCK-58 and gastrin (gastrin-17). There are only two distinct subtypes of CCK receptors, CCK₁ and CCK₂ receptors [64, 124], with some alternatively spliced forms most often identified in neoplastic cells. The CCK receptor subtypes are distinguished by their peptide selectivity, with the CCK₁ receptor requiring the carboxyl-terminal heptapeptide-amide that includes a sulfated tyrosine for high affinity and potency, while the CCK₂ receptor requires only the carboxyl-terminal tetrapeptide shared by each CCK and gastrin peptides. These receptors have characteristic and distinct distributions, with both present in both the central nervous system and peripheral tissues.

Class A Orphans in GtoPdb v.2023.1

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Table 1 lists a number of putative GPCRs identified by NC-IUPHAR [161], for which preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to a disease, or disorder. These GPCRs have recently been reviewed in detail [121]. The GPCRs in Table 1 are all Class A, rhodopsin-like GPCRs. Class A orphan GPCRs not listed in Table 1 are putative GPCRs with as-yet unidentified endogenous ligands.

Table 1: Class A orphan GPCRs with putative endogenous ligands

GPR3	GPR4	GPR6	GPR12	GPR15	GPR17	GPR20
GPR22	GPR26	GPR31	GPR34	GPR35	GPR37	GPR39
GPR50	GPR63	GPR65	GPR68	GPR75	GPR84	GPR87
GPR88	GPR132	GPR149	GPR161	GPR183	LGR4	LGR5
LGR6	MAS1	MRGPRD	MRGPRX1	MRGPRX2	P2RY10	TAAR2

In addition the orphan receptors GPR18, GPR55 and GPR119 which are reported to respond to endogenous agents analogous to the endogenous cannabinoid ligands have been grouped together (GPR18, GPR55 and GPR119).

Adhesion Class GPCRs in GtoPdb v.2023.1

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Adhesion GPCRs are structurally identified on the basis of a large extracellular region, similar to the Class B GPCR, but which is linked to the 7TM region by a GPCR autoproteolysis-inducing (GAIN) domain [10] containing a GPCR proteolysis site (GPS). The N-terminal extracellular region often shares structural homology with adhesive domains (e.g. cadherins, immunolobulin, lectins) facilitating inter- and matricellular interactions and leading to the term adhesion GPCR [104, 418]. Several receptors have been suggested to function as mechanosensors [320, 288, 396, 38]. Cryo-EM structures of the 7-transmembrane domain of several adhesion GPCRs have been determined recently [292, 21, 403, 212, 300, 302, 431, 293]. The nomenclature of these receptors was revised in 2015 as recommended by NC-IUPHAR and the Adhesion GPCR Consortium [125].

Class C Orphans in GtoPdb v.2023.1

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This set contains class C 'orphan' G protein coupled receptors where the endogenous ligand(s) is not known.

Corticotropin-releasing factor receptors in GtoPdb v.2023.1

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Corticotropin-releasing factor (CRF, nomenclature as agreed by the NC-IUPHAR subcommittee on Corticotropin-releasing Factor Receptors [34]) receptors are activated by the endogenous peptides corticotrophin-releasing hormone, a 41 amino-acid peptide, urocortin 1, 40 amino-acids, urocortin 2, 38 amino-acids and urocortin 3, 38 amino-acids. CRF₁ and CRF₂ receptors are activated non-selectively by CRH and UCN. CRF₂ receptors are selectively activated by UCN2 and UCN3. Binding to CRF receptors can be conducted using radioligands [¹²⁵I]Tyr⁰-CRF or [¹²⁵I]Tyr⁰-sauvagine with K_d values of 0.1-0.4 nM. CRF₁ and CRF₂ receptors are non-selectively antagonized by α-helical CRF, D-Phe-CRF-(12-41) and astressin. CRF₁ receptors are selectively antagonized by small molecules NBI27914, R121919, antalarmin, CP 154,526, CP 376,395. CRF₂ receptors are selectively antagonized by antisauvagine and astressin 2B.

Dopamine receptors in GtoPdb v.2023.1

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Dopamine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Dopamine Receptors [373]) are commonly divided into D₁-like (D₁ and D₅) and D₂-like (D₂, D₃ and D₄) families, where the endogenous agonist is dopamine.

Endothelin receptors in GtoPdb v.2023.1

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Endothelin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Endothelin Receptors [24]) are activated by the endogenous 21 amino-acid peptides endothelins 1-3 (endothelin-1, endothelin-2 and endothelin-3).

G protein-coupled estrogen receptor in GtoPdb v.2023.1

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The G protein-coupled estrogen receptor (GPER, nomenclature as agreed by the NC-IUPHAR Subcommittee on the G protein-coupled estrogen receptor [26]) was identified following observations of estrogen-evoked cyclic AMP signalling in breast cancer cells [2], which mirrored the differential expression of an orphan 7-transmembrane receptor GPR30 [6]. There are observations of both cell-surface and intracellular expression of the GPER receptor [29, 34]. Selective agonist/ antagonists for GPER have been characterized [26]. Antagonists of the nuclear estrogen receptor, such as fulvestrant [11], tamoxifen [29, 34] and raloxifene [25], as well as the flavonoid 'phytoestrogens' genistein and quercetin [18], are agonists of GPER. Reviews of GPER pharmacology have been published [26]. The roles of GPER in (patho)physiological systems throughout the body (cardiovascular, metabolic, endocrine, immune, reproductive) and in cancer have also been reviewed [26, 27, 20, 17, 9]. The GPER-selective agonist G-1 is currently in Phase I/II clinical trials for cancer (NCT04130516).

Free fatty acid receptors in GtoPdb v.2023.1

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Free fatty acid receptors (FFA, nomenclature as agreed by the NC-IUPHAR Subcommittee on free fatty acid receptors [116, 27]) are activated by free fatty acids. Long-chain saturated and unsaturated fatty acids (including C14.0 (myristic acid), C16:0 (palmitic acid), C18:1 (oleic acid), C18:2 (linoleic acid), C18:3, (α-linolenic acid), C20:4 (arachidonic acid), C20:5,n-3 (EPA) and C22:6,n-3 (docosahexaenoic acid)) activate FFA1 [9, 54, 64] and FFA4 receptors [45, 52, 94], while short chain fatty acids (C2 (acetic acid), C3 (propanoic acid), C4 (butyric acid) and C5 (pentanoic acid)) activate FFA2 [10, 66, 90] and FFA3 [10, 66] receptors. The crystal structure for agonist bound FFA1 has been described [113].

Class Frizzled GPCRs in GtoPdb v.2023.1

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Receptors of the Class Frizzled (FZD, nomenclature as agreed by the NC-IUPHAR subcommittee on the Class Frizzled GPCRs [180]), are GPCRs originally identified in Drosophila [20], which are highly conserved across species. While SMO shows structural resemblance to the 10 FZDs, it is functionally separated as it is involved in the Hedgehog signaling pathway [180]. SMO exerts its effects by activating heterotrimeric G proteins or stabilization of GLI by sequestering catalytic PKA subunits [186, 6, 58]. While SMO itself is bound by sterols and oxysterols [27, 94], FZDs are activated by WNTs, which are cysteine-rich lipoglycoproteins with fundamental functions in ontogeny and tissue homeostasis. FZD signalling was initially divided into two pathways, being either dependent on the accumulation of the transcription regulator β-catenin or being β-catenin-independent (often referred to as canonical vs. non-canonical WNT/FZD signalling, respectively). WNT stimulation of FZDs can, in cooperation with the low density lipoprotein receptors LRP5 (O75197) and LRP6 (O75581), lead to the inhibition of a constitutively active destruction complex, which results in the accumulation of β-catenin and subsequently its translocation to the nucleus. β-catenin, in turn, modifies gene transcription by interacting with TCF/LEF transcription factors. WNT/β-catenin-dependent signalling can also be activated by FZD subtype-specific WNT surrogates [138]. β-catenin-independent FZD signalling is far more complex with regard to the diversity of the activated pathways. WNT/FZD signalling can lead to the activation of heterotrimeric G proteins [34, 183, 155], the elevation of intracellular calcium [189], activation of cGMP-specific PDE6 [2] and elevation of cAMP as well as RAC-1, JNK, Rho and Rho kinase signalling [57]. Novel resonance energy transfer-based tools have allowed the study of the GPCR-like nature of FZDs in greater detail. Upon ligand stimulation, FZDs undergo conformational changes and signal via heterotrimeric G proteins [244, 245, 107, 179, 104]. Furthermore, the phosphoprotein Dishevelled constitutes a key player in WNT/FZD signalling towards planar-cell-polarity-like pathways. Importantly, FZDs exist in at least two distinct conformational states that regulate pathway selection [245]. As with other GPCRs, members of the Frizzled family are functionally dependent on the arrestin scaffolding protein for internalization [23], as well as for β-catenin-dependent [14] and -independent [91, 15] signalling. The pattern of cell signalling is complicated by the presence of additional ligands, which can enhance or inhibit FZD signalling (secreted Frizzled-related proteins (sFRP), Wnt-inhibitory factor (WIF), sclerostin or Dickkopf (DKK)), as well as modulatory (co)-receptors with Ryk, ROR1, ROR2 and Kremen, which may also function as independent signalling proteins.

Ghrelin receptor in GtoPdb v.2023.1

2023-05-10T17:45:24+01:00

The ghrelin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee for the Ghrelin receptor [19]) is activated by a 28 amino-acid peptide originally isolated from rat stomach, where it is cleaved from a 117 amino-acid precursor (GHRL, Q9UBU3). The human gene encoding the precursor peptide has 83% sequence homology to rat prepro-ghrelin, although the mature peptides from rat and human differ by only two amino acids [75]. Alternative splicing results in the formation of a second peptide, [des-Gln¹⁴]ghrelin with equipotent biological activity [50]. A unique post-translational modification (octanoylation of Ser³, catalysed by ghrelin Ο-acyltransferase (MBOAT4, Q96T53) [134] occurs in both peptides, essential for full activity in binding to ghrelin receptors in the hypothalamus and pituitary, and for the release of growth hormone from the pituitary [59]. Structure activity studies showed the first five N-terminal amino acids to be the minimum required for binding [4], and receptor mutagenesis has indicated overlap of the ghrelin binding site with those for small molecule agonists and allosteric modulators of ghrelin function [45]. An endogenous antagonist and inverse agonist called Liver enriched antimicrobial peptide 2 (Leap2), expressed primarily in hepatocytes and in enterocytes of the proximal intestine [36, 69] inhibits ghrelin receptor-induced GH secretion and food intake [36]. The secretion of Leap2 and ghrelin is inversely regulated under various metabolic conditions [72]. In cell systems, the ghrelin receptor is constitutively active [46], but this is abolished by a naturally occurring mutation (A204E) that results in decreased cell surface receptor expression and is associated with familial short stature [94].

Glucagon receptor family in GtoPdb v.2023.1

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The glucagon family of receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on the Glucagon receptor family [165]) are activated by the endogenous peptide (27-44 aa) hormones glucagon, glucagon-like peptide 1, glucagon-like peptide 2, glucose-dependent insulinotropic polypeptide (also known as gastric inhibitory polypeptide), GHRH and secretin. One common precursor (GCG) generates glucagon, glucagon-like peptide 1 and glucagon-like peptide 2 peptides [121]. For a recent review on the current understanding of the structures of GLP-1 and GLP-1R, the molecular basis of their interaction, and the associated signaling events see de Graaf et al., 2016 [90].

Glycoprotein hormone receptors in GtoPdb v.2023.1

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Glycoprotein hormone receptors (provisional nomenclature [47]) are activated by a non-covalent heterodimeric glycoprotein made up of a common α chain (glycoprotein hormone common alpha subunit CGA, P01215), with a unique β chain that confers the biological specificity to FSH, LH, hCG or TSH. There is binding cross-reactivity across the endogenous agonists for each of the glycoprotein hormone receptors. The deglycosylated hormones appear to exhibit reduced efficacy at these receptors [122, 31].

Gonadotrophin-releasing hormone receptors in GtoPdb v.2023.1

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GnRH₁ and GnRH₂ receptors (provisonal nomenclature [39], also called Type I and Type II GnRH receptor, respectively [85]) have been cloned from numerous species, most of which express two or three types of GnRH receptor [85, 84, 114]. GnRH I (p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) is a hypothalamic decapeptide also known as luteinizing hormone-releasing hormone, gonadoliberin, luliberin, gonadorelin or simply as GnRH. It is a member of a family of similar peptides found in many species [85, 84, 114] including GnRH II (pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH₂ (which is also known as chicken GnRH-II). Receptors for three forms of GnRH exist in some species but only GnRH I and GnRH II and their cognate receptors have been found in mammals [85, 84, 114]. GnRH₁ receptors are expressed by pituitary gonadotrophs, where they mediate the effects of GnRH on gonadotropin hormone synthesis and secretion that underpin central control of mammalian reproduction. GnRH analogues are used in assisted reproduction and to treat steroid hormone-dependent conditions [58]. Notably, agonists cause desensitization of GnRH-stimulated gonadotropin secretion and the consequent reduction in circulating sex steroids is exploited to treat hormone-dependent cancers of the breast, ovary and prostate [58]. GnRH₁ receptors are selectively activated by GnRH I and all lack the COOH-terminal tails found in other GPCRs. GnRH₂ receptors do have COOH-terminal tails and (where tested) are selective for GnRH II over GnRH I. GnRH₂ receptors are expressed by some primates but not by humans [88]. Phylogenetic classifications divide GnRH receptors into three [85] or five groups [130] and highlight examples of gene loss through evolution, with humans retaining only one ancient gene. The structure of the GnRH₁ receptor in complex with elagolix has been elucidated [133].

Histamine receptors in GtoPdb v.2023.1

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Histamine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Histamine Receptors [80, 174]) are activated by the endogenous ligand histamine. Marked species differences exist between histamine receptor orthologues [80]. The human and rat H₃ receptor genes are subject to significant splice variance [12]. The potency order of histamine at histamine receptor subtypes is H₃ = H₄ > H₂ > H₁ [174]. Some agonists at the human H₃ receptor display significant ligand bias [183]. Antagonists of all 4 histamine receptors have clinical uses: H₁ antagonists for allergies (e.g. cetirizine), H₂ antagonists for acid-reflux diseases (e.g. ranitidine), H₃ antagonists for narcolepsy (e.g. pitolisant/WAKIX; Registered) and H₄ antagonists for atopic dermatitis (e.g. adriforant; Phase IIa) [174] and vestibular neuritis (AUV) (SENS-111 (Seliforant, previously UR-63325), entered and completed vestibular neuritis (AUV) Phase IIa efficacy and safety trials, respectively) [217, 8].

Kisspeptin receptor in GtoPdb v.2023.1

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The kisspeptin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on the kisspeptin receptor [11]), like neuropeptide FF (NPFF), prolactin-releasing peptide (PrP) and QRFP receptors (provisional nomenclature) responds to endogenous peptides with an arginine-phenylalanine-amide (RFamide) motif. kisspeptin-54 (KP54, originally named metastin), kisspeptin-13 (KP13) and kisspeptin-10 (KP10) are biologically-active peptides cleaved from the KISS1 (Q15726) gene product. Kisspeptins have roles in, for example, cancer metastasis, fertility/puberty regulation and glucose homeostasis.

Leukotriene receptors in GtoPdb v.2023.1

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The leukotriene receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Leukotriene Receptors [35, 38]) are activated by the endogenous ligands leukotrienes (LT), synthesized from lipoxygenase metabolism of arachidonic acid. The human BLT₁ receptor is the high affinity LTB₄ receptor whereas the BLT₂ receptor in addition to being a low-affinity LTB₄ receptor also binds several other lipoxygenase-products, such as 12S-HETE, 12S-HPETE, 15S-HETE, and the thromboxane synthase product 12-hydroxyheptadecatrienoic acid. The BLT receptors mediate chemotaxis and immunomodulation in several leukocyte populations and are in addition expressed on non-myeloid cells, such as vascular smooth muscle and endothelial cells. In addition to BLT receptors, LTB₄ has been reported to bind to the peroxisome proliferator activated receptor (PPAR) α [201] and the vanilloid TRPV1 ligand-gated nonselective cation channel [223]. The crystal structure of the BLT₁ receptor was initially determined in complex with selective antagonists [141, 231] and has recently been extended to the cryo-electron microscopy structure of LTB₄-bound human BLT₁ receptor at 2.91 Å resolution [389]. The receptors for the cysteinyl-leukotrienes (i.e. LTC₄, LTD₄ and LTE₄) are termed CysLT₁ and CysLT₂ and exhibit distinct expression patterns in human tissues, mediating for example smooth muscle cell contraction, regulation of vascular permeability, and leukocyte activation. Quite recently, the the crystal structures of both receptors have been solved, the CysLT₁ in complex with zafirlukast and pranlukast [203] and the CysLT₂ in complex with three dual CysLT₁/CysLT₂ antagonists [122]. There is also evidence in the literature for additional CysLT receptor subtypes, derived from functional in vitro studies, radioligand binding and in mice lacking both CysLT₁ and CysLT₂ receptors [38]. Cysteinyl-leukotrienes have also been suggested to signal through the P2Y₁₂ receptor [99, 251, 280], GPR17 [60] and GPR99 [173].

Lysophospholipid (LPA) receptors in GtoPdb v.2023.1

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Lysophosphatidic acid (LPA) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid Receptors [62, 23, 91, 144]) are activated by the endogenous phospholipid LPA. The first receptor, LPA₁, was identified as ventricular zone gene-1 (vzg-1) [46], This discovery represented the beginning of the de-orphanisation of members of the endothelial differentiation gene (edg) family, as other LPA and sphingosine 1-phosphate (S1P) receptors were found. Five additional LPA receptors (LPA_2,3,4,5,6) have since been identified [91] and their gene nomenclature codified for human LPAR1, LPAR2, etc. (HUGO Gene Nomenclature Committee, HGNC) and Lpar1, Lpar2, etc. for mice (Mouse Genome Informatics Database, MGI) to reflect species and receptor function of their corresponding proteins. The crystal structure of LPA₁ [17, 80, 2] and LPA₆ [128] are solved and indicate that LPA accesses the extracellular binding pocket, consistent with its proposed delivery via autotaxin [17]. These studies have also implicated cross-talk with endocannabinoids via phosphorylated intermediates that can also activate these receptors. The binding affinities to LPA₁ of unlabeled, natural LPA and anandamide phosphate (AEAp) were measured using backscattering interferometry (pK_d = 9) [92, 115]. Utilization of this method indicated affinities that were 77-fold lower than when measured using radioactivity-based protocols [143]. Targeted deletion of LPA receptors has clarified signalling pathways and identified physiological and pathophysiological roles. Multiple groups have independently published validation of all six LPA receptors described in these tables, and further validation was achieved using a distinct read-out via a novel TGFα "shedding* assay [54]. LPA has been proposed to be a ligand for GPR35 [103], supported by a study revealing that LPA modulates macrophage function through GPR35 [60]. However chemokine (C-X-C motif) ligand 17 (CXCL17) is reported to be a ligand for GPR35/CXCR8 [85]. Moreover, LPA has also been described as an agonist for the transient receptor potential (Trp) ion channels TRPV1 [96] and TRPA1 [65]. All of these proposed non-GPCR receptor identities require confirmation and are not currently recognized as bona fide LPA receptors.

Melanin-concentrating hormone receptors in GtoPdb v.2023.1

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Melanin-concentrating hormone (MCH) receptors (provisional nomenclature as recommended by NC-IUPHAR [32]) are activated by an endogenous nonadecameric cyclic peptide identical in humans and rats (DFDMLRCMLGRVYRPCWQV; mammalian MCH) generated from a precursor (PMCH, P20382), which also produces neuropeptide EI and neuropeptide GE.

Melanocortin receptors in GtoPdb v.2023.1

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Melanocortin receptors (provisional nomenclature as recommended by NC-IUPHAR [41]) are activated by members of the melanocortin family (α-MSH, β-MSH and γ-MSH forms; δ form is not found in mammals) and adrenocorticotrophin (ACTH). Endogenous antagonists include agouti and agouti-related protein. ACTH(1-24) was approved by the US FDA as a diagnostic agent for adrenal function test. setmelanotide was approved by the US FDA for weight management in patients with POMC, PCSK1 or LEPR defiency, bremelanotide was approved by the US FDA for generalized hypoactive sexual desire disorder in premenopausal women, and NDP-MSH (afamelanotide) was approved by the EMA for the treatment of erythropoietic protoporphyria. Several synthetic melanocortin receptor agonists are under clinical development.

Melatonin receptors in GtoPdb v.2023.1

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Melatonin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Melatonin Receptors [40]) are activated by the endogenous ligands melatonin and clinically used drugs like ramelteon, agomelatine and tasimelteon.

Metabotropic glutamate receptors in GtoPdb v.2023.1

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Metabotropic glutamate (mGlu) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Metabotropic Glutamate Receptors [351]) are a family of G protein-coupled receptors activated by the neurotransmitter glutamate [140]. The mGlu family is composed of eight members (named mGlu1 to mGlu₈) which are divided in three groups based on similarities of agonist pharmacology, primary sequence and G protein coupling to effector: Group-I (mGlu₁ and mGlu₅), Group-II (mGlu₂ and mGlu₃) and Group-III (mGlu₄, mGlu₆, mGlu₇ and mGlu₈) (see Further reading).

Structurally, mGlu are composed of three juxtaposed domains: a core G protein-activating seven-transmembrane domain (TM), common to all GPCRs, is linked via a rigid cysteine-rich domain (CRD) to the Venus Flytrap domain (VFTD), a large bi-lobed extracellular domain where glutamate binds. mGlu form constitutive dimers, cross-linked by a disulfide bridge. The structures of the VFTD of mGlu₁, mGlu₂, mGlu₃, mGlu₅ and mGlu₇ have been solved [200, 275, 268, 403]. The structure of the 7 transmembrane (TM) domains of both mGlu1 and mGlu5 have been solved, and confirm a general helical organisation similar to that of other GPCRs, although the helices appear more compacted [88, 433, 62]. Recent advances in cryo-electron microscopy have provided structures of full-length mGlu receptor homodimers [217, 191] and heterodimers [91]. Studies have revealed the possible formation of heterodimers between either group-I receptors, or within and between group-II and -III receptors [89]. First characterised in transfected cells, co-localisation and specific pharmacological properties suggest the existence of such heterodimers in the brain [270, 440, 145, 283, 259, 218]. Beyond heteromerisation with other mGlu receptor subtypes, increasing evidence suggests mGlu receptors form heteromers and larger order complexes with class A GPCRs (reviewed in [140]).

The endogenous ligands of mGlu are L-glutamic acid, L-serine-O-phosphate, N-acetylaspartylglutamate (NAAG) and L-cysteine sulphinic acid. Group-I mGlu receptors may be activated by 3,5-DHPG and (S)-3HPG [30] and antagonised by (S)-hexylhomoibotenic acid [235]. Group-II mGlu receptors may be activated by LY389795 [269], LY379268 [269], eglumegad [354, 434], DCG-IV and (2R,3R)-APDC [355], and antagonised by eGlu [170] and LY307452 [425, 105]. Group-III mGlu receptors may be activated by L-AP4 and (R,S)-4-PPG [130]. An example of an antagonist selective for mGlu receptors is LY341495, which blocks mGlu₂ and mGlu₃ at low nanomolar concentrations, mGlu₈ at high nanomolar concentrations, and mGlu₄, mGlu₅, and mGlu₇ in the micromolar range [185]. In addition to orthosteric ligands that directly interact with the glutamate recognition site, allosteric modulators that bind within the TM domain have been described. Negative allosteric modulators are listed separately. The positive allosteric modulators most often act as ‘potentiators’ of an orthosteric agonist response, without significantly activating the receptor in the absence of agonist.

Motilin receptor in GtoPdb v.2023.1

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Motilin receptors (provisional nomenclature) are activated by motilin, a 22 amino-acid peptide derived from a precursor (MLN, P12872), which may also generate a motilin-associated peptide. There are significant species differences in the structure of motilin and its receptor, and in the functions of motilin. In humans and large mammals such as dog, activation of these receptors by motilin released from endocrine cells in the duodenal mucosa during fasting, induces propulsive phase III movements. This activity is associated with promoting hunger in humans. In humans and other mammals drugs and other non-peptide compounds which activate the motilin receptor may generate a more long-lasting ability to increase cholinergic activity within the upper gut, to promote upper gastrointestinal motility; this activity is suggested to be responsible for the gastrointestinal prokinetic effects of certain macrolide antibacterials (often called motilides; e.g. erythromycin, azithromycin), although for many of these molecules the evidence is sparse. Relatively high doses may induce vomiting and in humans, nausea.

Neuromedin U receptors in GtoPdb v.2023.1

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Neuromedin U receptors (provisional nomenclature as recommended by NC-IUPHAR [30]) are activated by the endogenous 25 amino acid peptide neuromedin U (neuromedin U-25, NmU-25), a peptide originally isolated from pig spinal cord [92]. In humans, NmU-25 appears to be the sole product of a precursor gene (NMU, P48645) showing a broad tissue distribution, but which is expressed at highest levels in the upper gastrointestinal tract, CNS, bone marrow and fetal liver. Much shorter versions of NmU are found in some species, but not in human, and are derived at least in some instances from the proteolytic cleavage of the longer NmU. Despite species differences in NmU structure, the C-terminal region (particularly the C-terminal pentapeptide) is highly conserved and contains biological activity. Neuromedin S (neuromedin S-33) has also been identified as an endogenous agonist [97]. NmS-33 is, as its name suggests, a 33 amino-acid product of a precursor protein derived from a single gene and contains an amidated C-terminal heptapeptide identical to NmU. NmS-33 appears to activate NMU receptors with equivalent potency to NmU-25.

Neuropeptide FF/neuropeptide AF receptors in GtoPdb v.2023.1

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The Neuropeptide FF receptor family contains two subtypes, NPFF1 and NPFF2 (provisional nomenclature [12]), which exhibit high affinities for neuropeptide FF (NPFF, O15130) and RFamide related peptides (RFRP: precursor gene symbol NPVF, Q9HCQ7). NPFF1 is broadly distributed in the central nervous system with the highest levels found in the limbic system and the hypothalamus. NPFF2 is present in high density in the superficial layers of the mammalian spinal cord where it is involved in nociception and modulation of opioid functions.

Neuropeptide S receptor in GtoPdb v.2023.1

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The neuropeptide S receptor (NPS receptor) responds to the 20 amino-acid peptide neuropeptide S derived from a precursor (NPS, P0C0P6). NPS activates its receptor at low nanomolar concentrations elevating intracellular cAMP and calcium levels [71]. Currently, some peptidic and small molecule NPS receptor antagonists are available as research tools [27, 79, 8, 59]. No NPS receptor ligands are currently used clinically.

Neuropeptide W/neuropeptide B receptors in GtoPdb v.2023.1

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The neuropeptide BW receptor 1 (NPBW1, provisional nomenclature [6]) is activated by two 23-amino-acid peptides, neuropeptide W (neuropeptide W-23) and neuropeptide B (neuropeptide B-23) [22, 7]. C-terminally extended forms of the peptides (neuropeptide W-30 and neuropeptide B-29) also activate NPBW1 [2]. Unique to both forms of neuropeptide B is the N-terminal bromination of the first tryptophan residue, and it is from this post-translational modification that the nomenclature NPB is derived. These peptides were first identified from bovine hypothalamus and therefore are classed as neuropeptides. Endogenous variants of the peptides without the N-terminal bromination, des-Br-neuropeptide B-23 and des-Br-neuropeptide B-29, were not found to be major components of bovine hypothalamic tissue extracts. The NPBW2 receptor is activated by the short and C-terminal extended forms of neuropeptide W and neuropeptide B [2].

Neuropeptide Y receptors in GtoPdb v.2023.1

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Neuropeptide Y (NPY) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Neuropeptide Y Receptors [158]) are activated by the endogenous peptides neuropeptide Y, neuropeptide Y-(3-36), peptide YY, PYY-(3-36) and pancreatic polypeptide (PP). The receptor originally identified as the Y3 receptor has been identified as the CXCR4 chemokine recepter (originally named LESTR, [139]). The y6 receptor is a functional gene product in mouse, absent in rat, but contains a frame-shift mutation in primates producing a truncated non-functional gene [84]. Three-dimensional structures have been determined for subtype active receptors Y₁, Y₂ and Y₄ [211, 114] and inactive antagonist bound Y₁ and Y₂ receptors [240, 210]. Many of the agonists exhibit differing degrees of selectivity dependent on the species examined. For example, the potency of PP is greater at the rat Y₄receptor than at the human receptor [62]. In addition, many agonists lack selectivity for individual subtypes, but can exhibit comparable potency against pairs of NPY receptor subtypes, or have not been examined for activity at all subtypes. [¹²⁵I]-PYY or [¹²⁵I]-NPY can be used to label Y₁, Y₂, Y₅ and y₆ subtypes non-selectively, while [¹²⁵I][cPP(1-7), NPY(19-23), Ala³¹, Aib³², Gln³⁴]hPP may be used to label Y₅ receptors preferentially (note that cPP denotes chicken peptide sequence and hPP is the human sequence).

Neurotensin receptors in GtoPdb v.2023.1

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Neurotensin receptors (nomenclature as recommended by NC-IUPHAR [39]) are activated by the endogenous tridecapeptide neurotensin (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu) derived from a precursor (NTS, 30990), which also generates neuromedin N, an agonist at the NTS₂ receptor. [³H]neurotensin (human, mouse, rat) and [¹²⁵I]neurotensin (human, mouse, rat) may be used to label NTS₁ and NTS₂ receptors at 0.1-0.3 and 3-5 nM concentrations respectively.

Hydroxycarboxylic acid receptors in GtoPdb v.2023.1

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The hydroxycarboxylic acid family of receptors (ENSFM00500000271913, nomenclature as agreed by the NC-IUPHAR Subcommittee on Hydroxycarboxylic acid receptors [36, 12]) respond to organic acids, including the endogenous hydroxy carboxylic acids 3-hydroxy butyric acid and L-lactic acid, as well as the lipid lowering agents nicotinic acid (niacin), acipimox and acifran [53, 60, 65]. These receptors were provisionally described as nicotinic acid receptors, although nicotinic acid shows submicromolar potency at HCA₂receptors only and is unlikely to be the natural ligand [60, 65].

Opioid receptors in GtoPdb v.2023.1

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Opioid and opioid-like receptors are activated by a variety of endogenous peptides including [Met]enkephalin (met), [Leu]enkephalin (leu), β-endorphin (β-end), α-neodynorphin, dynorphin A (dynA), dynorphin B (dynB), big dynorphin (Big dyn), nociceptin/orphanin FQ (N/OFQ); endomorphin-1 and endomorphin-2 are also potential endogenous peptides. The Greek letter nomenclature for the opioid receptors, μ, δ and κ, is well established, and NC-IUPHAR considers this nomenclature appropriate, along with the symbols spelled out (mu, delta, and kappa), and the acronyms, MOP, DOP, and KOP [124, 101, 92]. However the acronyms MOR, DOR and KOR are still widely used in the literature. The human N/OFQ receptor, NOP, is considered 'opioid-related' rather than opioid because, while it exhibits a high degree of structural homology with the conventional opioid receptors [304], it displays a distinct pharmacology. Currently there are numerous clinically used drugs, such as morphine and many other opioid analgesics, as well as antagonists such as naloxone. The majority of clinically used opiates are relatively selective μ agonists or partial agonists, though there are some μ/κ compounds, such as butorphanol, in clinical use. κ opioid agonists, such as the alkaloid nalfurafine and the peripherally acting peptide difelikefalin, are in clinical use for itch.

Orexin receptors in GtoPdb v.2023.1

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Orexin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Orexin receptors [43]) are activated by the endogenous polypeptides orexin-A and orexin-B (also known as hypocretin-1 and -2; 33 and 28 aa) derived from a common precursor, preproorexin or orexin precursor, by proteolytic cleavage and some typical peptide modifications [117]. Orexin signaling has been associated with regulation of sleep and wakefulness, reward and addiction, appetite and feeding, pain gating, stress response, anxiety and depression. Currently the orexin receptor ligands in clinical use are the dual orexin receptor antagonists suvorexant and lemborexant and daridorexant, which are used as hypnotics, and several dual and OX₂-selective antagonists are under development. Multiple orexin agonists are in development for the treatment of narcolepsy and other sleep disorders. Orexin receptor 3D structures have been solved [146, 144, 55, 126, 47, 109, 7, 145].

P2Y receptors in GtoPdb v.2023.1

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P2Y receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [3, 5, 189]) are activated by the endogenous ligands ATP, ADP, UTP, UDP, UDP-glucose and adenosine. The eight mammalian P2Y receptors are activated by distinct nucleotides: P2Y₁, P2Y₁₁, P2Y₁₂ and P2Y₁₃ are activated by adenosine-nucleotides; P2Y₂, P2Y₄ can be activated by both adenosine and uridine nucleotides, with some species-specific differences; P2Y₆ is mainly activated by UDP; P2Y₁₄ is preferentially activated by sugar-uracil nucleotides. The missing numbers in the receptor nomenclature refer either to non-mammalian orthologs or receptors having some sequence homology to P2Y receptors but for which there is no functional evidence of responsiveness to nucleotides [380]. Based on their G protein coupling P2Y receptors can be divided into two subfamilies: P2Y₁, P2Y₂, P2Y₄, P2Y₆ and P2Y₁₁ receptors couple via Gq proteins to stimulate phospholipase C followed by increases in inositol phosphates and mobilization of Ca²⁺ from intracellular stores. P2Y₁₁ receptors couple in addition to Gs proteins followed by increased adenylate cyclase activity. In contrast, P2Y₁₂, P2Y₁₃, and P2Y₁₄ receptors signal primarily through activation of Gi proteins and inhibition of adenylate cyclase activity or control of ion channel activity [380]. Clinically used drugs acting on these receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y₂ receptor subtype, approved in Japan and South Korea for the management of dry eye disease [238], and the P2Y₁₂ receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [52, 320].

Parathyroid hormone receptors in GtoPdb v.2023.1

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The parathyroid hormone receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Parathyroid Hormone Receptors [50]) are class B G protein-coupled receptors. The parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor (PTH1 receptor) is activated by precursor-derived peptides: PTH (84 amino acids), and PTHrP (141 amino-acids) and related peptides (PTH-(1-34), PTHrP-(1-36)). The parathyroid hormone 2 receptor (PTH2 receptor) is activated by the precursor-derived peptide TIP39 (39 amino acids). [¹²⁵I]PTH may be used to label both PTH1 and PTH2 receptors. The structure of a long-active PTH analogue (LA-PTH, an hybrid of PTH-(1-13) and PTHrP-(14-36)) bound to the PTH1 receptor-G_s complex has been resolved by cryo-electron microscopy [148]. Another structure of a PTH-(1-34) analog bound to a thermostabilized inactive PTH1 receptor has been obtained with X-ray crytallography [35].

QRFP receptor in GtoPdb v.2023.1

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The human gene encoding the QRFP receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on the QRFP receptor [19]; QRFPR, formerly known as the Peptide P518 receptor), previously designated as an orphan GPCR receptor was identified in 2001 by Lee et al. from a hypothalamus cDNA library [17]. However, the reported cDNA (AF411117) is a chimera with bases 1-127 derived from chromosome 1 and bases 155-1368 derived from chromosome 4. When corrected, QRFPR (also referred to as SP9155 or AQ27) encodes a 431 amino acid protein that shares sequence similarities in the transmembrane spanning regions with other peptide receptors. These include neuropeptide FF2 (38%), neuropeptide Y₂ (37%) and galanin Gal₁ (35%) receptors. QRFP receptor was identified as a Gs-coupled GPCR [6, 14] that's activated by the endogenous peptides QRFP43 (43RFa) and QRFP26 (26RFa) [6, 14, 11]. However, Gq- and Gi/o-mediated signaling was also reported [11, 25]. Two naturally occurring mutations in the human QRFP receptor lead to distinct and opposite 26RFa-evoked signaling bias [20].

Platelet-activating factor receptor in GtoPdb v.2023.1

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Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is an ether phospholipid mediator associated with platelet coagulation, but also subserves inflammatory roles. The PAF receptor (provisional nomenclature recommended by NC-IUPHAR [38]) is activated by PAF and other suggested endogenous ligands are oxidized phosphatidylcholine [74] and lysophosphatidylcholine [98]. It may also be activated by bacterial lipopolysaccharide [91].

Prokineticin receptors in GtoPdb v.2023.1

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Prokineticin receptors, PKR₁ and PKR₂ (provisional nomenclature as recommended by NC-IUPHAR [26]) respond to the cysteine-rich 81-86 amino-acid peptides prokineticin-1 (also known as endocrine gland-derived vascular endothelial growth factor, mambakine) and prokineticin-2 (protein Bv8 homologue). An orthologue of PROK1 from black mamba (Dendroaspis polylepis) venom, mamba intestinal toxin 1 (MIT1, [71]) is a potent, non-selective agonist at prokineticin receptors [46], while Bv8, an orthologue of PROK2 from amphibians (Bombina sp., [49]), is equipotent at recombinant PKR₁ and PKR₂ [53], and has high potency in macrophage chemotaxis assays, which are lost in PKR₁-null mice.

Prostanoid receptors in GtoPdb v.2023.1

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Prostanoid receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Prostanoid Receptors [701]) are activated by the endogenous ligands prostaglandins PGD₂, PGE₁, PGE₂ , PGF_2α, PGH₂, prostacyclin [PGI₂] and thromboxane A₂. Differences and similarities between human and rodent prostanoid receptor orthologues, and their specific roles in pathophysiologic conditions are reviewed in [452]. Measurement of the potency of PGI₂ and thromboxane A₂ is hampered by their instability in physiological salt solution; they are often replaced by cicaprost and U46619, respectively, in receptor characterization studies.

Proteinase-activated receptors in GtoPdb v.2023.1

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Proteinase-activated receptors (PARs, nomenclature as agreed by the NC-IUPHAR Subcommittee on Proteinase-activated Receptors [39]) are unique members of the GPCR superfamily activated by proteolytic cleavage of their amino terminal exodomains. Agonist proteinase-induced hydrolysis unmasks a tethered ligand (TL) at the exposed amino terminus, which acts intramolecularly at the binding site in the body of the receptor to effect transmembrane signalling. TL sequences at human PAR1-4 are SFLLRN-NH₂, SLIGKV-NH₂, TFRGAP-NH₂ and GYPGQV-NH₂, respectively. With the exception of PAR3, synthetic peptides with these sequences (as carboxyl terminal amides) are able to act as agonists at their respective receptors. Several proteinases, including neutrophil elastase, cathepsin G and chymotrypsin can have inhibitory effects at PAR1 and PAR2 such that they cleave the exodomain of the receptor without inducing activation of Gαq-coupled calcium signalling, thereby preventing activation by activating proteinases but not by agonist peptides. Neutrophil elastase (NE) cleavage of PAR1 and PAR2 can however activate MAP kinase signaling by exposing a TL that is different from the one revealed by trypsin [87]. PAR2 activation by NE regulates inflammation and pain responses [115, 76] and triggers mucin secretion from airway epithelial cells [116].

Relaxin family peptide receptors in GtoPdb v.2023.1

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Relaxin family peptide receptors (RXFP, nomenclature as agreed by the NC-IUPHAR Subcommittee on Relaxin family peptide receptors [23, 119]) may be divided into two pairs, RXFP1/2 and RXFP3/4. Endogenous agonists at these receptors are heterodimeric peptide hormones structurally related to insulin: relaxin-1, relaxin, relaxin-3 (also known as INSL7), insulin-like peptide 3 (INSL3) and INSL5. Species homologues of relaxin have distinct pharmacology and relaxin interacts with RXFP1, RXFP2 and RXFP3, whereas mouse and rat relaxin selectively bind to and activate RXFP1 [260]. relaxin-3 is the ligand for RXFP3 but it also binds to RXFP1 and RXFP4 and has differential affinity for RXFP2 between species [259]. INSL5 is the ligand for RXFP4 but is a weak antagonist of RXFP3. relaxin and INSL3 have multiple complex binding interactions with RXFP1 [267] and RXFP2 [132] which direct the N-terminal LDLa modules of the receptors together with a linker domain to act as a tethered ligand to direct receptor signaling [262]. INSL5 and relaxin-3 interact with their receptors using distinct residues in their B-chains for binding, and activation, respectively [321, 152].

Somatostatin receptors in GtoPdb v.2023.1

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Somatostatin (somatotropin release inhibiting factor) is an abundant neuropeptide, which acts on five subtypes of somatostatin receptor (SST₁-SST₅; nomenclature as agreed by the NC-IUPHAR Subcommittee on Somatostatin Receptors [98]). Activation of these receptors produces a wide range of physiological effects throughout the body including the inhibition of secretion of many hormones. Endogenous ligands for these receptors are somatostatin-14 (SRIF-14) and somatostatin-28 (SRIF-28). cortistatin-14 has also been suggested to be an endogenous ligand for somatostatin receptors [61].

Tachykinin receptors in GtoPdb v.2023.1

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Tachykinin receptors (provisional nomenclature as recommended by NC-IUPHAR [91]) are activated by the endogenous peptides substance P (SP), neurokinin A (NKA; previously known as substance K, neurokinin α, neuromedin L), neurokinin B (NKB; previously known as neurokinin β, neuromedin K), neuropeptide K and neuropeptide γ (N-terminally extended forms of neurokinin A). The neurokinins (A and B) are mammalian members of the tachykinin family, which includes peptides of mammalian and nonmammalian origin containing the consensus sequence: Phe-x-Gly-Leu-Met. Marked species differences in in vitro pharmacology exist for all three receptors, in the context of nonpeptide ligands. Antagonists such as aprepitant and fosaprepitant were approved by FDA and EMA, in combination with other antiemetic agents, for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy.

Thyrotropin-releasing hormone receptors in GtoPdb v.2023.1

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Thyrotropin-releasing hormone (TRH) receptors (provisional nomenclature as recommended by NC-IUPHAR [14]) are activated by the endogenous tripeptide TRH (pGlu-His-ProNH2). TRH and TRH analogues fail to distinguish TRH₁ and TRH₂ receptors [29]. [³H]TRH (human, mouse, rat) is able to label both TRH₁ and TRH₂ receptors with K_d values of 13 and 9 nM respectively. Synthesis and biology of ring-modified L-Histidine containing TRH analogues has been reported [23].

Trace amine receptor in GtoPdb v.2023.1

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Trace amine-associated receptors were discovered from a search for novel 5-HT receptors [9], where 15 mammalian orthologues were identified and divided into two families. The TA₁ receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee for the Trace amine receptor [58]) has affinity for the endogenous trace amines tyramine, β-phenylethylamine and octopamine in addition to the classical amine dopamine [9]. Emerging evidence suggests that TA₁ is a modulator of monoaminergic activity in the brain [94] with TA₁ and dopamine D₂ receptors shown to form constitutive heterodimers when co-expressed [30]. In addition to trace amines, receptors can be activated by amphetamine-like psychostimulants, and endogenous thyronamines.

Urotensin receptor in GtoPdb v.2023.1

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The urotensin-II (U-II) receptor (UT, nomenclature as agreed by the NC-IUPHAR Subcommittee on the Urotensin receptor [26, 36, 94]) is activated by the endogenous dodecapeptide urotensin-II, originally isolated from the urophysis, the endocrine organ of the caudal neurosecretory system of teleost fish [7, 93]. Several structural forms of U-II exist in fish and amphibians [94]. The goby orthologue was used to identify U-II as the cognate ligand for the predicted receptor encoded by the rat gene gpr14 [2, 20, 63, 69, 72]. Human urotensin-II, an 11-amino-acid peptide [20], retains the cyclohexapeptide sequence of goby U-II that is thought to be important in ligand binding [61, 53, 10]. This sequence is also conserved in the deduced amino-acid sequence of rat urotensin-II (14 amino-acids) and mouse urotensin-II (14 amino-acids), although the N-terminal is more divergent from the human sequence [19]. A second endogenous ligand for the UT has been discovered in rat [86]. This is the urotensin II-related peptide, an octapeptide that is derived from a different gene, but shares the C-terminal sequence (CFWKYCV) common to U-II from other species. Identical sequences to rat urotensin II-related peptide are predicted for the mature mouse and human peptides [32]. UT exhibits relatively high sequence identity with somatostatin, opioid and galanin receptors [94]. The urotensinergic system displays an unprecedented repertoire of four or five ancient UT in some vertebrate lineages and five U-II family peptides in teleost fish [91].

Vasopressin and oxytocin receptors in GtoPdb v.2023.1

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Vasopressin (AVP) and oxytocin (OT) receptors (nomenclature as recommended by NC-IUPHAR [94]) are activated by the endogenous cyclic nonapeptides vasopressin and oxytocin. These peptides are derived from precursors which also produce neurophysins (neurophysin I for oxytocin; neurophysin II for vasopressin). Vasopressin and oxytocin differ at only 2 amino acids (positions 3 and 8). There are metabolites of these neuropeptides that may be biologically active [69].

VIP and PACAP receptors in GtoPdb v.2023.1

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Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Vasoactive Intestinal Peptide Receptors [65, 66]) are activated by the endogenous peptides VIP, PACAP-38, PACAP-27, peptide histidine isoleucineamide (PHI), peptide histidine methionineamide (PHM) and peptide histidine valine (PHV). VPAC₁ and VPAC₂ receptors display comparable affinity for the PACAP peptides, PACAP-27 and PACAP-38, and VIP, whereas PACAP-27 and PACAP-38 are >100 fold more potent than VIP as agonists of most isoforms of the PAC₁ receptor. However, one splice variant of the human PAC₁ receptor has been reported to respond to PACAP-38, PACAP-27 and VIP with comparable affinity [30]. PG 99-465 [117] has been used as a selective VPAC₂receptor antagonist in a number of physiological studies, but has been reported to have significant activity at VPAC₁ and PAC₁ receptors [36]. The selective PAC₁ receptor agonist maxadilan, was extracted from the salivary glands of sand flies (Lutzomyia longipalpis) and has no sequence homology to VIP or the PACAP peptides [118]. Two deletion variants of maxadilan, M65 [183] and Max.d.4 [119] have been reported to be PAC₁ receptor antagonists, but these peptides have not been extensively characterised.

Calcium- and sodium-activated potassium channels (K_Ca, K_Na) in GtoPdb v.2023.1

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Calcium- and sodium- activated potassium channels are members of the 6TM family of K channels which comprises the voltage-gated K_Vsubfamilies, including the KCNQ subfamily, the EAG subfamily (which includes hERG channels), the Ca²⁺-activated Slo subfamily (actually with 6 or 7TM) and the Ca²⁺- and Na⁺-activated SK subfamily (nomenclature as agreed by the NC-IUPHAR Subcommittee on Calcium- and sodium-activated potassium channels [126]). As for the 2TM family, the pore-forming a subunits form tetramers and heteromeric channels may be formed within subfamilies (e.g. K_V1.1 with K_V1.2; KCNQ2 with KCNQ3).

Cyclic nucleotide-regulated channels (CNG) in GtoPdb v.2023.1

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Cyclic nucleotide-gated (CNG) channels are responsible for signalling in the primary sensory cells of the vertebrate visual and olfactory systems. CNG channels are voltage-independent cation channels formed as tetramers. Each subunit has 6TM, with the pore-forming domain between TM5 and TM6. CNG channels were first found in rod photoreceptors [83, 120], where light signals through rhodopsin and transducin to stimulate phosphodiesterase and reduce intracellular cyclic GMP level. This results in a closure of CNG channels and a reduced ‘dark current’. Similar channels were found in the cilia of olfactory neurons [181] and the pineal gland [71]. The cyclic nucleotides bind to a domain in the C terminus of the subunit protein: other channels directly binding cyclic nucleotides include hyperolarisation-activated, cyclic nucleotide-gated channels (HCN), ether-a-go-go and certain plant potassium channels.

The HCN channels are cation channels that are activated by hyperpolarisation at voltages negative to ~-50 mV. The cyclic nucleotides cyclic AMP and cyclic GMP directly bind to the cyclic nucleotide-binding domain of HCN channels and shift their activation curves to more positive voltages, thereby enhancing channel activity. HCN channels underlie pacemaker currents found in many excitable cells including cardiac cells and neurons [65, 192]. In native cells, these currents have a variety of names, such as I_h, I_q and I_f. The four known HCN channels have six transmembrane domains and form tetramers. It is believed that the channels can form heteromers with each other, as has been shown for HCN1 and HCN4 [2]. High resolution structural studies of CNG and HCN channels has provided insight into the the gating processes of these channels [139, 146, 140]. A standardised nomenclature for CNG and HCN channels has been proposed by the NC-IUPHAR Subcommittee on voltage-gated ion channels [108].

GABA_A receptors in GtoPdb v.2023.1

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The GABA_A receptor is a ligand-gated ion channel of the Cys-loop family that includes the nicotinic acetylcholine, 5-HT₃ and strychnine-sensitive glycine receptors. GABA_A receptor-mediated inhibition within the CNS occurs by fast synaptic transmission, sustained tonic inhibition and temporally intermediate events that have been termed 'GABA_A, slow' [45]. GABA_A receptors exist as pentamers of 4TM subunits that form an intrinsic anion selective channel. Sequences of six α, three β, three γ, one δ, three ρ, one ε, one π and one θ GABA_A receptor subunits have been reported in mammals [281, 237, 238, 288]. The π-subunit is restricted to reproductive tissue. Alternatively spliced versions of many subunits exist (e.g. α4- and α6- (both not functional) α5-, β2-, β3- and γ2), along with RNA editing of the α3 subunit [71]. The three ρ-subunits, (ρ1-3) function as either homo- or hetero-oligomeric assemblies [365, 50]. Receptors formed from ρ-subunits, because of their distinctive pharmacology that includes insensitivity to bicuculline, benzodiazepines and barbiturates, have sometimes been termed GABA_C receptors [365], but they are classified as GABA_A receptors by NC-IUPHAR on the basis of structural and functional criteria [16, 237, 238].

Many GABA_A receptor subtypes contain α-, β- and γ-subunits with the likely stoichiometry 2α.2β.1γ [170, 237]. It is thought that the majority of GABA_A receptors harbour a single type of α- and β -subunit variant. The α1β2γ2 hetero-oligomer constitutes the largest population of GABA_A receptors in the CNS, followed by the α2β3γ2 and α3β3γ2 isoforms. Receptors that incorporate the α4- α5-or α6-subunit, or the β1-, γ1-, γ3-, δ-, ε- and θ-subunits, are less numerous, but they may nonetheless serve important functions. For example, extrasynaptically located receptors that contain α6- and δ-subunits in cerebellar granule cells, or an α4- and δ-subunit in dentate gyrus granule cells and thalamic neurones, mediate a tonic current that is important for neuronal excitability in response to ambient concentrations of GABA [211, 275, 84, 19, 293]. GABA binding occurs at the β+/α- subunit interface and the homologous γ+/α- subunits interface creates the benzodiazepine site. A second site for benzodiazepine binding has recently been postulated to occur at the α+/β- interface ([257]; reviewed by [287]). The particular α-and γ-subunit isoforms exhibit marked effects on recognition and/or efficacy at the benzodiazepine site. Thus, receptors incorporating either α4- or α6-subunits are not recognised by ‘classical’ benzodiazepines, such as flunitrazepam (but see [362]). The trafficking, cell surface expression, internalisation and function of GABA_A receptors and their subunits are discussed in detail in several recent reviews [52, 141, 190, 322] but one point worthy of note is that receptors incorporating the γ2 subunit (except when associated with α5) cluster at the postsynaptic membrane (but may distribute dynamically between synaptic and extrasynaptic locations), whereas those incorporating the δ subunit appear to be exclusively extrasynaptic.

NC-IUPHAR [16, 237, 3, 2] class the GABA_A receptors according to their subunit structure, pharmacology and receptor function. Currently, eleven native GABA_A receptors are classed as conclusively identified (i.e., α1β2γ2, α2βγ2, α3βγ2, α4βγ2, α4β2δ, α4β3δ, α5βγ2, α6βγ2, α6β2δ, α6β3δ and ρ) with further receptor isoforms occurring with high probability, or only tentatively [237, 238]. It is beyond the scope of this Guide to discuss the pharmacology of individual GABA_A receptor isoforms in detail; such information can be gleaned in the reviews [16, 96, 170, 175, 144, 281, 218, 237, 238, 284, 9, 10]. Agents that discriminate between α-subunit isoforms are noted in the table and additional agents that demonstrate selectivity between receptor isoforms, for example via β-subunit selectivity, are indicated in the text below. The distinctive agonist and antagonist pharmacology of ρ receptors is summarised in the table and additional aspects are reviewed in [365, 50, 146, 225].

Several high-resolution cryo-electron microscopy structures have been described in which the full-length human α1β3γ2L GABA_A receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (γ-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam [200].

Glycine receptors in GtoPdb v.2023.1

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The inhibitory glycine receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on Glycine Receptors) is a member of the Cys-loop superfamily of transmitter-gated ion channels that includes the GABA_A, nicotinic acetylcholine and 5-HT₃ receptors and Zn²⁺- activated channels. The glycine receptor is expressed either as a homo-pentamer of α subunits, or a complex of 4α and 1β subunits [131], that contains an intrinsic anion channel. Four differentially expressed isoforms of the α-subunit (α1-α4) and one variant of the β-subunit (β1, GLRB, P48167) have been identified by genomic and cDNA cloning. Further diversity originates from alternative splicing of the primary gene transcripts for α1 (α1^INS and α1^del), α2 (α2A and α2B), α3 (α3S and α3L) and β (βΔ7) subunits and by mRNA editing of the α2 and α3 subunit [20, 84, 94]. Both α2 splicing and α3 mRNA editing can produce subunits (i.e., α2B and α3P185L) with enhanced agonist sensitivity. Predominantly, the adult form of the receptor contains α1 (or α3) and β subunits whereas the immature form is mostly composed of only α2 subunits [79]. The α4 subunit is a pseudogene in humans [66]. High resolution molecular structures are available for α1 homomeric, α3 homomeric, and αβ hteromeric receptors in a variety of ligand-induced conformations [19, 129, 19, 48, 49, 50]. As in other Cys-loop receptors, the orthosteric binding site for agonists and the competitive antagonist strychnine is formed at the interfaces between the subunits’ extracellular domains. Inclusion of the β-subunit in the pentameric glycine receptor contributes to agonist binding, reduces single channel conductance and alters pharmacology. The β-subunit also anchors the receptor, via an amphipathic sequence within the large intracellular loop region, to gephyrin. This a cytoskeletal attachment protein that binds to a number of subsynaptic proteins involved in cytoskeletal structure and thus clusters and anchors hetero-oligomeric receptors to the synapse [55, 89]. G protein βγ subunits enhance the open state probability of native and recombinant glycine receptors by association with domains within the large intracellular loop [125, 124]. Intracellular chloride concentration modulates the kinetics of native and recombinant glycine receptors [97]. Intracellular Ca²⁺ appears to increase native and recombinant glycine receptor affinity, prolonging channel open events, by a mechanism that does not involve phosphorylation [26]. Extracellular Zn²⁺ potentiates GlyR function at nanomolar concentrations [87]. and causes inhibition at higher micromolar concentrations (17).

Inwardly rectifying potassium channels (K_IR) in GtoPdb v.2023.1

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The 2TM domain family of K channels are also known as the inward-rectifier K channel family. This family includes the strong inward-rectifier K channels (K_ir2.x) that are constitutively active, the G-protein-activated inward-rectifier K channels (K_ir3.x) and the ATP-sensitive K channels (K_ir6.x, which combine with sulphonylurea receptors (SUR1-3)). The pore-forming α subunits form tetramers, and heteromeric channels may be formed within subfamilies (e.g. K_ir3.2 with K_ir3.3).

Ionotropic glutamate receptors in GtoPdb v.2023.1

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The ionotropic glutamate receptors comprise members of the NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid) and kainate receptor classes, named originally according to their preferred, synthetic, agonist [36, 94, 157]. Receptor heterogeneity within each class arises from the homo-oligomeric, or hetero-oligomeric, assembly of distinct subunits into cation-selective tetramers. Each subunit of the tetrameric complex comprises an extracellular amino terminal domain (ATD), an extracellular ligand binding domain (LBD), 3 TM domains (M1, M3 and M4), a channel lining re-entrant 'p-loop' (M2) located between M1 and M3 and an intracellular carboxy- terminal domain (CTD) [101, 70, 109, 157, 84]. The X-ray structure of a homomeric ionotropic glutamate receptor (GluA2- see below) has recently been solved at 3.6Å resolution [145] and although providing the most complete structural information current available may not representative of the subunit arrangement of, for example, the heteromeric NMDA receptors [73]. It is beyond the scope of this supplement to discuss the pharmacology of individual ionotropic glutamate receptor isoforms in detail; such information can be gleaned from [36, 68, 32, 79, 43, 116, 25, 67, 157, 114, 115, 165]. Agents that discriminate between subunit isoforms are, where appropriate, noted in the tables and additional compounds that distinguish between receptor isoforms are indicated in the text below.

The classification of glutamate receptor subunits has been re-addressed by NC-IUPHAR [29]. The scheme developed recommends a nomenclature for ionotropic glutamate receptor subunits that is adopted here.

NMDA receptors
NMDA receptors assemble as obligate heteromers that may be drawn from GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A and GluN3B subunits. Alternative splicing can generate eight isoforms of GluN1 with differing pharmacological properties. Various splice variants of GluN2B, 2C, 2D and GluN3A have also been reported. Activation of NMDA receptors containing GluN1 and GluN2 subunits requires the binding of two agonists, glutamate to the S1 and S2 regions of the GluN2 subunit and glycine to S1 and S2 regions of the GluN1 subunit [42, 26]. The minimal requirement for efficient functional expression of NMDA receptors in vitro is a di-heteromeric assembly of GluN1 and at least one GluN2 subunit variant, as a dimer of heterodimers arrangement in the extracellular domain [49, 101, 73]. However, more complex tri-heteromeric assemblies, incorporating multiple subtypes of GluN2 subunit, or GluN3 subunits, can be generated in vitro and occur in vivo. The NMDA receptor channel commonly has a high relative permeability to Ca²⁺ and is blocked, in a voltage-dependent manner, by Mg²⁺ such that at resting potentials the response is substantially inhibited.

AMPA and Kainate receptors
AMPA receptors assemble as homomers, or heteromers, that may be drawn from GluA1, GluA2, GluA3 and GluA4 subunits. Transmembrane AMPA receptor regulatory proteins (TARPs) of class I (i.e. γ2, γ3, γ4 and γ8) act, with variable stoichiometry, as auxiliary subunits to AMPA receptors and influence their trafficking, single channel conductance gating and pharmacology (reviewed in [44, 105, 155, 66]). Functional kainate receptors can be expressed as homomers of GluK1, GluK2 or GluK3 subunits. GluK1-3 subunits are also capable of assembling into heterotetramers (e.g. GluK1/K2; [89, 121, 120]). Two additional kainate receptor subunits, GluK4 and GluK5, when expressed individually, form high affinity binding sites for kainate, but lack function, but can form heteromers when expressed with GluK1-3 subunits (e.g. GluK2/K5; reviewed in [121, 67, 120]). Kainate receptors may also exhibit 'metabotropic' functions [89, 133]. As found for AMPA receptors, kainate receptors are modulated by auxiliary subunits (Neto proteins, [120, 90]). An important function difference between AMPA and kainate receptors is that the latter require extracellular Na⁺ and Cl^- for their activation [12, 122]. RNA encoding the GluA2 subunit undergoes extensive RNA editing in which the codon encoding a p-loop glutamine residue (Q) is converted to one encoding arginine (R). This Q/R site strongly influences the biophysical properties of the receptor. Recombinant AMPA receptors lacking RNA edited GluA2 subunits are: (1) permeable to Ca²⁺; (2) blocked by intracellular polyamines at depolarized potentials causing inward rectification (the latter being reduced by TARPs); (3) blocked by extracellular argiotoxin and joro spider toxins and (4) demonstrate higher channel conductances than receptors containing the edited form of GluA2 [141, 65]. GluK1 and GluK2, but not other kainate receptor subunits, are similarly edited and broadly similar functional characteristics apply to kainate receptors lacking either an RNA edited GluK1, or GluK2, subunit [89, 120]. Native AMPA and kainate receptors displaying differential channel conductances, Ca²⁺ permeabilites and sensitivity to block by intracellular polyamines have been identified [31, 65, 93]. GluA1-4 can exist as two variants generated by alternative splicing (termed ‘flip’ and ‘flop’) that differ in their desensitization kinetics and their desensitization in the presence of cyclothiazide which stabilises the nondesensitized state. TARPs also stabilise the non-desensitized conformation of AMPA receptors and facilitate the action of cyclothiazide [105]. Splice variants of GluK1-3 also exist which affects their trafficking [89, 120].

P2X receptors in GtoPdb v.2023.1

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P2X receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2X Receptors [49, 146]) have a trimeric topology [118, 128, 144, 197] with two putative TM domains per P2X subunit, gating primarily Na⁺, K⁺ and Ca²⁺, exceptionally Cl^-. The Nomenclature Subcommittee has recommended that for P2X receptors, structural criteria should be the initial basis for nomenclature where possible. X-ray crystallography indicates that functional P2X receptors are trimeric and three agonist molecules are required to bind to a single trimeric assembly in order to activate it [118, 144, 95, 103, 177]. Native receptors may occur as either homotrimers (e.g. P2X1 in smooth muscle) or heterotrimers (e.g. P2X2:P2X3 in the nodose ganglion [280], P2X1:P2X5 in mouse cortical astrocytes [162], and P2X2:P2X5 in mouse dorsal root ganglion, spinal cord and mid pons [53, 234]. P2X2, P2X4 and P2X7 receptor activation can lead to influx of large cationic molecules, such as NMDG⁺, Yo-Pro, ethidium or propidium iodide [211]. The permeability of the P2X7 receptor is modulated by the amount of cholesterol in the plasma membrane [193]. The hemi-channel pannexin-1 was initially implicated in the action of P2X7 [212], but not P2X2, receptors [41], but this interpretation is probably misleading [215]. Convincing evidence now supports the view that the activated P2X7 receptor is immediately permeable to large cationic molecules, but influx proceeds at a much slower pace than that of the small cations Na⁺, K⁺, and Ca²⁺ [66].

Transient Receptor Potential channels (TRP) in GtoPdb v.2023.1

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The TRP superfamily of channels (nomenclature as agreed by NC-IUPHAR [176, 1072]), whose founder member is the Drosophila Trp channel, exists in mammals as six families; TRPC, TRPM, TRPV, TRPA, TRPP and TRPML based on amino acid homologies. TRP subunits contain six putative TM domains and assemble as homo- or hetero-tetramers to form cation selective channels with diverse modes of activation and varied permeation properties (reviewed by [730]). Established, or potential, physiological functions of the individual members of the TRP families are discussed in detail in the recommended reviews and in a number of books [401, 686, 1155, 256]. The established, or potential, involvement of TRP channels in disease [1126] is reviewed in [448, 685], [688] and [464], together with a special edition of Biochemica et Biophysica Acta on the subject [685]. Additional disease related reviews, for pain [633], stroke [1135], sensation and inflammation [988], itch [130], and airway disease [310, 1051], are available. The pharmacology of most TRP channels has been advanced in recent years. Broad spectrum agents are listed in the tables along with more selective, or recently recognised, ligands that are flagged by the inclusion of a primary reference. See Rubaiy (2019) for a review of pharmacological tools for TRPC1/C4/C5 channels [805]. Most TRP channels are regulated by phosphoinostides such as PtIns(4,5)P₂ although the effects reported are often complex, occasionally contradictory, and likely to be dependent upon experimental conditions, such as intracellular ATP levels (reviewed by [1009, 689, 801]). Such regulation is generally not included in the tables.When thermosensitivity is mentioned, it refers specifically to a high Q10 of gating, often in the range of 10-30, but does not necessarily imply that the channel's function is to act as a 'hot' or 'cold' sensor. In general, the search for TRP activators has led to many claims for temperature sensing, mechanosensation, and lipid sensing. All proteins are of course sensitive to energies of binding, mechanical force, and temperature, but the issue is whether the proposed input is within a physiologically relevant range resulting in a response.

TRPA (ankyrin) family

TRPA1 is the sole mammalian member of this group (reviewed by [293]). TRPA1 activation of sensory neurons contribute to nociception [414, 890, 602]. Pungent chemicals such as mustard oil (AITC), allicin, and cinnamaldehyde activate TRPA1 by modification of free thiol groups of cysteine side chains, especially those located in its amino terminus [575, 60, 365, 577]. Alkenals with α, β-unsaturated bonds, such as propenal (acrolein), butenal (crotylaldehyde), and 2-pentenal can react with free thiols via Michael addition and can activate TRPA1. However, potency appears to weaken as carbon chain length increases [26, 60]. Covalent modification leads to sustained activation of TRPA1. Chemicals including carvacrol, menthol, and local anesthetics reversibly activate TRPA1 by non-covalent binding [424, 511, 1081, 1080]. TRPA1 is not mechanosensitive under physiological conditions, but can be activated by cold temperatures [425, 212]. The electron cryo-EM structure of TRPA1 [740] indicates that it is a 6-TM homotetramer. Each subunit of the channel contains two short ‘pore helices’ pointing into the ion selectivity filter, which is big enough to allow permeation of partially hydrated Ca²⁺ ions.

TRPC (canonical) family

Members of the TRPC subfamily (reviewed by [284, 778, 18, 4, 94, 446, 739, 70]) fall into the subgroups outlined below. TRPC2 is a pseudogene in humans. It is generally accepted that all TRPC channels are activated downstream of G_q/11-coupled receptors, or receptor tyrosine kinases (reviewed by [765, 953, 1072]). A comprehensive listing of G-protein coupled receptors that activate TRPC channels is given in [4]. Hetero-oligomeric complexes of TRPC channels and their association with proteins to form signalling complexes are detailed in [18] and [447]. TRPC channels have frequently been proposed to act as store-operated channels (SOCs) (or compenents of mulimeric complexes that form SOCs), activated by depletion of intracellular calcium stores (reviewed by [741, 18, 770, 820, 1121, 157, 726, 64, 158]). However, the weight of the evidence is that they are not directly gated by conventional store-operated mechanisms, as established for Stim-gated Orai channels. TRPC channels are not mechanically gated in physiologically relevant ranges of force. All members of the TRPC family are blocked by 2-APB and SKF96365 [347, 346]. Activation of TRPC channels by lipids is discussed by [70]. Important progress has been recently made in TRPC pharmacology [805, 619, 436, 102, 851, 191, 291]. TRPC channels regulate a variety of physiological functions and are implicated in many human diseases [295, 71, 885, 1031, 1025, 154, 103, 561, 913, 409].

TRPC1/C4/C5 subgroup
TRPC1 alone may not form a functional ion channel [229]. TRPC4/C5 may be distinguished from other TRP channels by their potentiation by micromolar concentrations of La³⁺. TRPC2 is a pseudogene in humans, but in other mammals appears to be an ion channel localized to microvilli of the vomeronasal organ. It is required for normal sexual behavior in response to pheromones in mice. It may also function in the main olfactory epithelia in mice [1114, 723, 724, 1115, 539, 1168, 1109].

TRPC3/C6/C7 subgroup
All members are activated by diacylglycerol independent of protein kinase C stimulation [347].

TRPM (melastatin) family

Members of the TRPM subfamily (reviewed by [275, 346, 741, 1151]) fall into the five subgroups outlined below.

TRPM1/M3 subgroup
In darkness, glutamate released by the photoreceptors and ON-bipolar cells binds to the metabotropic glutamate receptor 6 , leading to activation of Go . This results in the closure of TRPM1. When the photoreceptors are stimulated by light, glutamate release is reduced, and TRPM1 channels are more active, resulting in cell membrane depolarization. Human TRPM1 mutations are associated with congenital stationary night blindness (CSNB), whose patients lack rod function. TRPM1 is also found melanocytes. Isoforms of TRPM1 may present in melanocytes, melanoma, brain, and retina. In melanoma cells, TRPM1 is prevalent in highly dynamic intracellular vesicular structures [398, 708]. TRPM3 (reviewed by [714]) exists as multiple splice variants which differ significantly in their biophysical properties. TRPM3 is expressed in somatosensory neurons and may be important in development of heat hyperalgesia during inflammation (see review [941]). TRPM3 is frequently coexpressed with TRPA1 and TRPV1 in these neurons. TRPM3 is expressed in pancreatic beta cells as well as brain, pituitary gland, eye, kidney, and adipose tissue [713, 940]. TRPM3 may contribute to the detection of noxious heat [1017].

TRPM2
TRPM2 is activated under conditions of oxidative stress (respiratory burst of phagocytic cells). The direct activators are calcium, adenosine diphosphate ribose (ADPR) [970] and cyclic ADPR (cADPR) [1118]. As for many ion channels, PI(4,5)P2 must also be present [1109]. Numerous splice variants of TRPM2 exist which differ in their activation mechanisms [239]. Recent studies have reported structures of human (hs) TRPM2, which demonstrate two ADPR binding sites in hsTRPM2, one in the N-terminal MHR1/2 domain and the other in the C-terminal NUDT9-H domain. In addition, one Ca²⁺ binding site in the intracellular S2-S3 loop is revealed and proposed to mediate Ca²⁺ binding that induces conformational changes leading the ADPR-bound closed channel to open [387, 1027]. Meanwhile, a quadruple-residue motif (979FGQI982) was identified as the ion selectivity filter and a gate to control ion permeation in hsTRPM2 [1120]. TRPM2 is involved in warmth sensation [848], and contributes to several diseases [76]. TRPM2 interacts with extra synaptic NMDA receptors (NMDAR) and enhances NMDAR activity in ischemic stroke [1164]. Activation of TRPM2 in macrophages promotes atherosclerosis [1165, 1147]. Moreover, silica nanoparticles induce lung inflammation in mice via ROS/PARP/TRPM2 signaling-mediated lysosome impairment and autophagy dysfunction [1028]. Recent studies have designed various compounds for their potential to selectively inhibit the TRPM2 channel, including ACA derivatives A23, and 2,3-dihydroquinazolin-4(1H)-one derivatives [1137, 1139].

TRPM4/5 subgroup
TRPM4 and TRPM5 have the distinction within all TRP channels of being impermeable to Ca²⁺ [1072]. A splice variant of TRPM4 (i.e.TRPM4b) and TRPM5 are molecular candidates for endogenous calcium-activated cation (CAN) channels [327]. TRPM4 is active in the late phase of repolarization of the cardiac ventricular action potential. TRPM4 deletion or knockout enhances beta adrenergic-mediated inotropy [593]. Mutations are associated with conduction defects [404, 593, 879]. TRPM4 has been shown to be an important regulator of Ca²⁺ entry in to mast cells [993] and dendritic cell migration [52]. TRPM5 in taste receptor cells of the tongue appears essential for the transduction of sweet, amino acid and bitter stimuli [537] TRPM5 contributes to the slow afterdepolarization of layer 5 neurons in mouse prefrontal cortex [513]. Both TRPM4 and TRPM5 are required transduction of taste stimuli [246].

TRPM6/7 subgroup
TRPM6 and 7 combine channel and enzymatic activities (‘chanzymes’) [172]. These channels have the unusual property of permeation by divalent (Ca²⁺, Mg²⁺, Zn²⁺) and monovalent cations, high single channel conductances, but overall extremely small inward conductance when expressed to the plasma membrane. They are inhibited by internal Mg²⁺ at ~0.6 mM, around the free level of Mg²⁺ in cells. Whether they contribute to Mg²⁺ homeostasis is a contentious issue. PIP2 is required for TRPM6 and TRPM7 activation [810, 1077]. When either gene is deleted in mice, the result is embryonic lethality [413, 1065]. The C-terminal kinase region of TRPM6 and TRPM7 is cleaved under unknown stimuli, and the kinase phosphorylates nuclear histones [479, 480]. TRPM7 is responsible for oxidant- induced Zn²⁺ release from intracellular vesicles [3] and contributes to intestinal mineral absorption essential for postnatal survival [622]. The putative metal transporter proteins CNNM1-4 interact with TRPM7 and regulate TRPM7 channel activity [40, 467].

TRPM8
Is a channel activated by cooling and pharmacological agents evoking a ‘cool’ sensation and participates in the thermosensation of cold temperatures [63, 178, 224] reviewed by [1011, 562, 457, 649]. Direct chemical agonists include menthol and icilin[1086]. Besides, linalool can promote ERK phosphorylation in human dermal microvascular endothelial cells, down-regulate intracellular ATP levels, and activate TRPM8 [68]. Recent studies have found that TRPM8 has typical S4-S5 connectomes with clear selective filters and exowell rings [512], and have identified cryo-electron microscopy structures of mouse TRPM8 in closed, intermediate, and open states along the ligand- and PIP₂-dependent gated pathways [1111]. Moreover, the last 36 amino acids at the carboxyl terminal of TRPM8 are key protein sequences for TRPM8's temperature-sensitive function [194]. TRPM8 deficiency reduced the expression of S100A9 and increased the expression of HNF4α in the liver of mice, which reduced inflammation and fibrosis progression in mice with liver fibrosis, and helped to alleviate the symptoms of bile duct disease [556]. Channel deficiency also shortens the time of hypersensitivity reactions in migraine mouse models by promoting the recovery of normal sensitivity [12]. A cyclic peptide DeC‐1.2 was designed to inhibit ligand activation of TRPM8 but not cold activation, which can eliminate the side effects of cold dysalgesia in oxaliplatin-treated mice without changing body temperature [9]. Analysis of clinical data shows that TRPM8-specific blockers WS12 can reduce tumor growth in colorectal cancer xenografted mice by reducing transcription and activation of Wnt signaling regulators and β-catenin and its target oncogenes, such as C-Myc and Cyclin D1 [732].

TRPML (mucolipin) family

The TRPML family [782, 1132, 775, 1084, 190] consists of three mammalian members (TRPML1-3). TRPML channels are probably restricted to intracellular vesicles and mutations in the gene (MCOLN1) encoding TRPML1 (mucolipin-1) cause the neurodegenerative disorder mucolipidosis type IV (MLIV) in man. TRPML1 is a cation selective ion channel that is important for sorting/transport of endosomes in the late endocytotic pathway and specifically, fission from late endosome-lysosome hybrid vesicles and lysosomal exocytosis [822]. TRPML2 and TRPML3 show increased channel activity in low luminal sodium and/or increased luminal pH, and are activated by similar small molecules [319, 147, 877]. A naturally occurring gain of function mutation in TRPML3 (i.e. A419P) results in the varitint waddler (Va) mouse phenotype (reviewed by [782, 690]).

TRPP (polycystin) family

The TRPP family (reviewed by [216, 214, 300, 1061, 374]) or PKD2 family is comprised of PKD2 (PC2), PKD2L1 (PC2L1), PKD2L2 (PC2L2), which have been renamed TRPP1, TRPP2 and TRPP3, respectively [1072]. It should also be noted that the nomenclature of PC2 was TRPP2 in old literature. However, PC2 has been uniformed to be called TRPP2 [345]. PKD2 family channels are clearly distinct from the PKD1 family, whose function is unknown. PKD1 and PKD2 form a hetero-oligomeric complex with a 1:3 ratio. [905]. Although still being sorted out, TRPP family members appear to be 6TM spanning nonselective cation channels.

TRPV (vanilloid) family

Members of the TRPV family (reviewed by [995]) can broadly be divided into the non-selective cation channels, TRPV1-4 and the more calcium selective channels TRPV5 and TRPV6.

TRPV1-V4 subfamily
TRPV1 is involved in the development of thermal hyperalgesia following inflammation and may contribute to the detection of noxius heat (reviewed by [762, 882, 922]). Numerous splice variants of TRPV1 have been described, some of which modulate the activity of TRPV1, or act in a dominant negative manner when co-expressed with TRPV1 [844]. The pharmacology of TRPV1 channels is discussed in detail in [329] and [1015]. TRPV2 is probably not a thermosensor in man [736], but has recently been implicated in innate immunity [547]. Functional TRPV2 expression is described in placental trophoblast cells of mouse [204]. TRPV3 and TRPV4 are both thermosensitive. There are claims that TRPV4 is also mechanosensitive, but this has not been established to be within a physiological range in a native environment [127, 530].

TRPV5/V6 subfamily
TRPV5 and TRPV6 are highly expressed in placenta, bone, and kidney. Under physiological conditions, TRPV5 and TRPV6 are calcium selective channels involved in the absorption and reabsorption of calcium across intestinal and kidney tubule epithelia (reviewed by [1057, 205, 651, 270]).TRPV6 is reported to play a key role in calcium transport in the mouse placenta [1056].

Two-pore domain potassium channels (K_2P) in GtoPdb v.2023.1

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The 4TM family of K channels mediate many of the background potassium currents observed in native cells. They are open across the physiological voltage-range and are regulated by a wide array of neurotransmitters and biochemical mediators. The pore-forming α-subunit contains two pore loop (P) domains and two subunits assemble to form one ion conduction pathway lined by four P domains. It is important to note that single channels do not have two pores but that each subunit has two P domains in its primary sequence; hence the name two-pore domain, or K_2P channels (and not two-pore channels). Some of the K_2P subunits can form heterodimers across subfamilies (e.g. K_2P3.1 with K_2P9.1). The nomenclature of 4TM K channels in the literature is still a mixture of IUPHAR and common names. The suggested division into subfamilies, described in the More detailed introduction, is based on similarities in both structural and functional properties within subfamilies and this explains the "common abbreviation" nomenclature in the tables below.

Voltage-gated calcium channels (Ca_V) in GtoPdb v.2023.1

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Ca²⁺ channels are voltage-gated ion channels present in the membrane of most excitable cells. The nomenclature for Ca²⁺channels was proposed by [131] and approved by the NC-IUPHAR Subcommittee on Ca²⁺ channels [72]. Most Ca²⁺ channels form hetero-oligomeric complexes. The α1 subunit is pore-forming and provides the binding site(s) for practically all agonists and antagonists. The 10 cloned α1-subunits can be grouped into three families: (1) the high-voltage activated dihydropyridine-sensitive (L-type, Ca_V1.x) channels; (2) the high- to moderate-voltage activated dihydropyridine-insensitive (Ca_V2.x) channels and (3) the low-voltage-activated (T-type, Ca_V3.x) channels. Each α1 subunit has four homologous repeats (I-IV), each repeat having six transmembrane domains (S1-S6) and a pore-forming region between S5 and S6. Voltage-dependent gating is driven by the membrane spanning S4 segment, which contains highly conserved positive charges that respond to changes in membrane potential. All of the α1-subunit genes give rise to alternatively spliced products. At least for high-voltage activated channels, it is likely that native channels comprise co-assemblies of α1, β and α2-δ subunits. The γ subunits have not been proven to associate with channels other than the α1s skeletal muscle Ca_v1.1 channel. The α2-δ1 and α2-δ2 subunits bind gabapentin and pregabalin.

Voltage-gated potassium channels (K_v) in GtoPdb v.2023.1

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The 6TM family of K channels comprises the voltage-gated K_Vsubfamilies, the EAG subfamily (which includes hERG channels), the Ca²⁺-activated Slo subfamily (actually with 7TM, termed BK) and the Ca²⁺-activated SK subfamily. These channels possess a pore-forming α subunit that comprise tetramers of identical subunits (homomeric) or of different subunits (heteromeric). Heteromeric channels can only be formed within subfamilies (e.g. K_v1.1 with K_v1.2; K_v7.2 with K_v7.3). The pharmacology largely reflects the subunit composition of the functional channel.K_v7 channelsK_v7.1-K_v7.5 (KCNQ1-5) K⁺ channels are voltage-gated K⁺ channels with major roles in neurons, muscle cells and epithelia where they underlie physiologically important K⁺ currents, such as the neuronal M-current and the cardiac IKs. Genetic deficiencies in all five KCNQ genes result in human excitability disorders, including epilepsy, autism spectrum disorders, cardiac arrhythmias and deafness. Thanks to the recent knowledge of the structure and function of human KCNQ-encoded proteins, these channels are increasingly used as drug targets for treating diseases [326, 2, 767].

Voltage-gated sodium channels (Na_V) in GtoPdb v.2023.1

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Sodium channels are voltage-gated sodium-selective ion channels present in the membrane of most excitable cells. Sodium channels comprise of one pore-forming α subunit, which may be associated with either one or two β subunits [179]. α-Subunits consist of four homologous domains (I-IV), each containing six transmembrane segments (S1-S6) and a pore-forming loop. The positively charged fourth transmembrane segment (S4) acts as a voltage sensor and is involved in channel gating. The crystal structure of the bacterial NavAb channel has revealed a number of novel structural features compared to earlier potassium channel structures including a short selectivity filter with ion selectivity determined by interactions with glutamate side chains [278]. Interestingly, the pore region is penetrated by fatty acyl chains that extend into the central cavity which may allow the entry of small, hydrophobic pore-blocking drugs [278]. Auxiliary β1, β2, β3 and β4 subunits consist of a large extracellular N-terminal domain, a single transmembrane segment and a shorter cytoplasmic domain.

The nomenclature for sodium channels was proposed by Goldin et al., (2000) [146] and approved by the NC-IUPHAR Subcommittee on sodium channels (Catterall et al., 2005, [53]).

ZAC in GtoPdb v.2023.1

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The zinc-activated channel (ZAC, nomenclature as agreed by the NC-IUPHAR Subcommittee for the Zinc Activated Channel) is a member of the Cys-loop family that includes the nicotinic ACh, 5-HT₃, GABA_A and strychnine-sensitive glycine receptors [2, 3, 5]. The channel is likely to exist as a homopentamer of 4TM subunits that form an intrinsic cation selective channel equipermeable to Na⁺, K⁺ and Cs⁺, but impermeable to Ca²⁺ and Mg²⁺ [5]. ZAC displays constitutive activity that can be blocked by tubocurarine, TTFB and high concentrations of Ca²⁺ [5]. Although denoted ZAC, the channel is more potently activated by H⁺ and Cu²⁺, with greater and lesser efficacy than Zn²⁺, respectively [5]. Orthologs of the human ZACN gene are present in a wide range of mammalian genomes, but notably not in the mouse or rat genomes. [2, 3].

1A. Thyroid hormone receptors in GtoPdb v.2023.1

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Thyroid hormone receptors (TRs, nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [12, 2]) are nuclear hormone receptors of the NR1A family, with diverse roles regulating macronutrient metabolism, cognition and cardiovascular homeostasis. TRs are activated by thyroxine (T₄) and thyroid hormone (triiodothyronine). Once activated by a ligand, the receptor acts as a transcription factor either as a monomer, homodimer or heterodimer with members of the retinoid X receptor family. NH-3 has been described as an antagonist at TRs with modest selectivity for TRβ [42].

1F. Retinoic acid-related orphans in GtoPdb v.2023.1

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Retinoic acid receptor-related orphan receptors (ROR, nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [11, 3]) have yet to be assigned a deﬁnitive endogenous ligand, although RORα may be synthesized with a ‘captured’ agonist such as cholesterol [68, 67].

1H. Liver X receptor-like receptors in GtoPdb v.2023.1

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Liver X and farnesoid X receptors (LXR and FXR, nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [76, 3]) are members of a steroid analogue-activated nuclear receptor subfamily, which form heterodimers with members of the retinoid X receptor family. Endogenous ligands for LXRs include hydroxycholesterols (OHC), while FXRs appear to be activated by bile acids. In humans and primates, NR1H5P is a pseudogene. However, in other mammals, it encodes a functional nuclear hormone receptor that appears to be involved in cholesterol biosynthesis [80].

1I. Vitamin D receptor-like receptors in GtoPdb v.2023.1

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Vitamin D (VDR), Pregnane X (PXR) and Constitutive Androstane (CAR) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [50, 1]) are members of the NR1I family of nuclear receptors, which form heterodimers with members of the retinoid X receptor family. PXR and CAR are activated by a range of exogenous compounds, with no established endogenous physiological agonists, although high concentrations of bile acids and bile pigments activate PXR and CAR [50].

2A. Hepatocyte nuclear factor-4 receptors in GtoPdb v.2023.1

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The nomenclature of hepatocyte nuclear factor-4 receptors is agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [9, 3]. While linoleic acid has been identified as the endogenous ligand for HNF4α its function remains ambiguous [75]. HNF4γ has yet to be paired with an endogenous ligand.

2F. COUP-TF-like receptors in GtoPdb v.2023.1

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COUP-TF-like receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [7, 2]) have yet to be officially paired with an endogenous ligand.

3A. Estrogen receptors in GtoPdb v.2023.1

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Estrogen receptor (ER) activity regulates diverse physiological processes via transcriptional modulation of target genes [2]. The selection of target genes and the magnitude of the response, be it induction or repression, are determined by many factors, including the effect of the hormone ligand and DNA binding on ER structural conformation, and the local cellular regulatory environment. The cellular environment defines the specific complement of DNA enhancer and promoter elements present and the availability of coregulators to form functional transcription complexes. Together, these determinants control the resulting biological response.

3C. 3-Ketosteroid receptors in GtoPdb v.2023.1

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Steroid hormone receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [75, 218, 3]) are nuclear hormone receptors of the NR3 class, with endogenous agonists that may be divided into 3-hydroxysteroids (estrone and 17β-estradiol) and 3-ketosteroids (dihydrotestosterone [DHT], aldosterone, cortisol, corticosterone, progesterone and testosterone). For rodent GR and MR, the physiological ligand is corticosterone rather than cortisol.

Lanosterol biosynthesis pathway in GtoPdb v.2023.1

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Lanosterol is a precursor for cholesterol, which is synthesized primarily in the liver in a pathway often described as the mevalonate or HMG-CoA reductase pathway. The first two steps (formation of acetoacetyl CoA and the mitochondrial generation of (S)-3-hydroxy-3-methylglutaryl-CoA) are also associated with oxidation of fatty acids.

Other 7TM proteins in GtoPdb v.2023.1

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These proteins are predicted to have 7TM domains, but functional studies have yet to confirm them as G protein-coupled receptors.

GPR18, GPR55 and GPR119 in GtoPdb v.2023.1

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GPR18, GPR55 and GPR119 (provisional nomenclature), although showing little structural similarity to CB₁ and CB₂ cannabinoid receptors, respond to endogenous agents analogous to the endogenous cannabinoid ligands, as well as some natural/synthetic cannabinoid receptor ligands [104]. Although there are multiple reports to indicate that GPR18, GPR55 and GPR119 can be activated in vitro by N-arachidonoylglycine, lysophosphatidylinositol and N-oleoylethanolamide, respectively, there is a lack of evidence for activation by these lipid messengers in vivo. As such, therefore, these receptors retain their orphan status.

Taste 2 receptors in GtoPdb v.2023.1

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Taste 2 receptors or Bitter taste receptors (TAS2Rs) are G protein-coupled receptors expressed in oral sensory cells and a variety of non-gustatory tissues. The ~25 human TAS2Rs share low amino acid sequence identities with other GPCR families and are classified as broadly tuned "generalist" receptors with numerous, chemically diverse bitter agonists, as narrowly tuned "specialist" receptors with very few activators, as intermediately tuned receptors with an average number of agonists, or receptors specialized to interact with chemically defined activators [32]. The number of functional bitter taste receptor genes varies among species and orthologues might not be functionally conserved. Due to their expression in various tissues, the signal transduction of TAS2Rs is complex. Some TAS2Rs interact with drugs such as analgesic, anti-inflammatory, and antibacterial compounds. The specialist database BitterDB contains additional information on bitter compounds and receptors [14].

Acid-sensing (proton-gated) ion channels (ASICs) in GtoPdb v.2023.1

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Acid-sensing ion channels (ASICs, nomenclature as agreed by NC-IUPHAR [48, 2, 3]) are members of a Na⁺ channel superfamily that includes the epithelial Na⁺ channel (ENaC), the FMRF-amide activated channel (FaNaC) of invertebrates, the degenerins (DEG) of Caenorhabitis elegans, channels in Drosophila melanogaster and 'orphan' channels that include BLINaC [70] and INaC [72] that have also been named BASICs, for bile acid-activated ion channels [90]. ASIC subunits contain 2 TM domains and assemble as homo- or hetero-trimers [45, 41, 7, 94, 93, 77] to form proton-gated, voltage-insensitive, Na⁺ permeable, channels that are activated by levels of acidosis occurring in both physiological and pathophysiological conditions with ASIC3 also playing a role in mechanosensation (reviewed in [44, 89, 48, 69, 23]). Splice variants of ASIC1 [termed ASIC1a (ASIC, ASICα, BNaC2α) [84], ASIC1b (ASICβ, BNaC2β) [19] and ASIC1b2 (ASICβ2) [79]; note that ASIC1a is also permeable to Ca²⁺], ASIC2 [termed ASIC2a (MDEG1, BNaC1α, BNC1α) [66, 85, 40] and ASIC2b (MDEG2, BNaC1β) [56]] differ in the first third of the protein. Unlike ASIC2a (listed in table), heterologous expression of ASIC2b alone does not support H⁺-gated currents. A third member, ASIC3 (DRASIC, TNaC1) [83] is one of the most pH-sensitive isoforms (along with ASIC1a) and has the fastest activation and desensitisation kinetics, however can also carry small sustained currents. ASIC4 (SPASIC) evolved as a proton-sensitive channel but seems to have lost this function in mammals [58]. Mammalian ASIC4 does not support a proton-gated channel in heterologous expression systems but is reported to downregulate the expression of ASIC1a and ASIC3 [1, 43, 34, 54]. ASICs channels are primarily expressed in central (ASIC1a, -2a, 2b and -4) and peripheral neurons including nociceptors (ASIC1-3) where they participate in neuronal sensitivity to acidosis. Humans express, in contrast to rodents, ASIC3 also in the brain [27]. ASICs have also been detected in taste receptor cells (ASIC1-3)), photoreceptors and retinal cells (ASIC1-3), cochlear hair cells (ASIC1b), testis (hASIC3), pituitary gland (ASIC4), lung epithelial cells (ASIC1a and -3), urothelial cells, adipose cells (ASIC3), vascular smooth muscle cells (ASIC1-3), immune cells (ASIC1,-3 and -4) and bone (ASIC1-3) (ASIC distribution is reviewed in [55, 28, 42]). A neurotransmitter-like function of protons has been suggested, involving postsynaptically located ASICs of the CNS in functions such as learning and fear perception [35, 50, 97], responses to focal ischemia [91] and to axonal degeneration in autoimmune inflammation in a mouse model of multiple sclerosis [39], as well as seizures [98] and pain [89, 29, 30, 13, 32]. Heterologously expressed heteromultimers form ion channels with differences in kinetics, ion selectivity, pH- sensitivity and sensitivity to blockers that resemble some of the native proton activated currents recorded from neurones [56, 5, 38, 11]. In general, the known small molecule inhibitors of ASICs are non-selective or partially selective, whereas the venom peptide inhibitors have substantially higher selectivity and potency. Several clinically used drugs are known to inhibit ASICs, however they are generally more potent at other targets (e.g. amiloride at ENaCs, ibuprofen at COX enzymes) [68, 63]. The information in the tables below are for the effects of inhibitors on homomeric channels, for information of known effects on heteromeric channels see the comments below.

Epithelial sodium channel (ENaC) in GtoPdb v.2023.1

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OverviewThe epithelial sodium channels (ENaC) are located on the apical membrane of epithelial cells in the kidney tubules, lung, respiratory tract, male and female reproductive tracts, sweat and salivary glands, placenta, colon, and some other organs [10, 48, 14, 23, 22]. In these epithelia, Na⁺ ions flow from the extracellular fluid into the cytoplasm of epithelial cells via ENaC and are then pumped out of the cytoplasm into the interstitial fluid by the Na⁺/K⁺ ATPase located on the basolateral membrane [42]. As Na⁺ is one of the major electrolytes in the extracellular fluid (ECF), osmolarity change initiated by the Na⁺ flow is accompanied by a flow of water [7]. Thus, ENaC has a central role in regulating ECF volume and blood pressure, primarily via its function in the kidney [43]. The expression of ENaC subunits, hence its activity, is regulated by the renin-angiotensin-aldosterone system, and other factors involved in electrolyte homeostasis [43, 32].

The genetics of the hereditary systemic pseudohypoaldosteronism type-I revealed that the activity of ENaC is dependent on three subunits encoded by three genes [23, 12]. Within the protein superfamily that includes ENaC, the crystal structure of ASIC was determined first, revealing a trimeric structure with a large extracellular domain anchored in the membrane with a bundle of six TM helices (two TM helices/subunit) [3, 26]. The first 3D structure of human ENaC was determined by single-particle cryo-electron microscopy at a resolution of 3.7 Å [38]. A recent study improved the resolution to 3 Å [39]. These structures confirmed that ENaC has a 3D quaternary structure similar to ASIC. ENaC is assembled as a hetero-trimer with a clockwise order of α-γ-β subunit viewed from the top, as shown previously [13]. In contrast to ASIC1 which can assemble into a functional homotrimer, ENaC activity can be reconstituted fully only as a heterotrimer with an αβγ or a δβγ composition [29].

In the respiratory tract and female reproductive tract, large segments of the epithelia are composed of multi-ciliated cells. In these cells, ENaC is located along the entire length of the cilia that cover the cell surface [16]. Cilial location greatly increases ENaC density per cell surface and allows ENaC to serve as a sensitive regulator of osmolarity of the periciliary fluid throughout the whole depth of the fluid bathing the cilia [16]. In contrast to ENaC, CFTR (ion transporter defective in cystic fibrosis) is located on the non-cilial cell surface [16]. In the vas deferens segment of the male reproductive tract, the luminal surface is covered by microvilli and stereocilia projections with backbones composed of actin filament bundles [48]. In these cells, both ENaC and the water channel aquaporin AQP9 are localized on these projections and also in the basal and smooth muscle layers [48]. Thus, ENaC function regulates the volume of fluid lining epithelia essential for mucociliary clearance of respiratory airways, transport of germ cells, fertilization, implantation, and cell migration [37, 16, 23]. Genes and PhylogenyIn the human genome, there are four homologous genes (SCNN1A, SCNN1B, SCNN1D, and SCNN1G) that encode four proteins, α-, β-, γ-, and δ-ENaC that may be involved in the assembly of ENaC [11, 34, 47, 53]. These four subunits share 23-34% sequence identity and <20% identity with ASIC subunits [23]. The genes coding for all four ENaC subunits are present in all bony vertebrates with the exception of ray-finned fish genomes that have lost all ENaC genes. The mouse genome has lost the gene SCNN1D that codes for δ-ENaC [18, 23, 23]. The α-, β-, and γ-ENaC genes are also present in jawless vertebrates (e.g., lampreys) and cartilaginous fishes (e.g., sharks) [23]. Examination of the methylation patterns of the 5'-flanking region of SCNN1A, SCNN1B, and SCNN1G genes in human cells showed an inverse correlation between gene expression and DNA methylation, suggesting epigenetic transcriptional control of ENaC genes [41]. Channel biogenesis, assembly and functionThe expression of ENaC subunits is regulated primarily by aldosterone and many additional extracellular and intracellular factors [43, 31, 40]. Most of the studies indicate that the expression of the three subunits is not coordinated [9]. However, the transport of the subunits to the membrane is dependent on three intact subunits. Even a missense mutation in one subunit reduces the concentration of assembled channels on the cell surface [15].

ENaC is a constitutively active channel, i.e., the flow of Na⁺ ions is not dependent on an activating factor. Hence, heterologous cells expressing ENaC (e.g., Xenopus oocytes), must be maintained in a solution that contains amiloride to keep ENaC inhibited. To measure ENaC activity, the bath solution is switched to a solution without amiloride. ENaC has two major states: 1) Open, and 2) Closed. The probability of ENaC being in the open state is called ENaC open probability (Po). ENaC activity is regulated by a diverse array of factors that exert their effects by modifying, directly or indirectly, two major parameters: 1) The density of ENaC in the membrane; and 2) The channel open probability [27, 29]. The Po of ENaC is greatly decreased by external Na⁺ and this response is called Na⁺ self-inhibition [49, 4, 25].

An important aspect of ENaC regulation is that the α and the γ subunits have conserved serine protease cleavage sites in the extracellular segment [23]. Cleavage of these subunits by proteases such as furin and plasmin leads to the activation of ENaC [44, 30, 1].Diseases associated with ENaC mutationsMutations in any of the three genes (SCNN1A, SCNN1B, and SCNN1G) may cause partial or complete loss of ENaC activity, depending on the mutation [12, 20]. Such loss-of-function mutations are associated with a syndrome named "systemic" or "multi-system" autosomal recessive pseudohypoaldosteronism type I (PHA1B) [19, 12, 23, 16, 55, 46]. So far, no mutation has been found in the SCNN1D gene that causes PHA. PHA patients suffer from severe salt loss from all aldosterone target organs expressing ENaC, including kidney, sweat and salivary glands and respiratory tract. During infancy and early childhood, the severe electrolyte disturbances, dehydration and acidosis may require recurrent hospitalizations. The severity and frequency of salt-wasting episodes improve with age [21]. PHA1B is also associated with a dysfunctional female reproductive system [16, 6].

The carboxy-terminal of ENaC includes a short consensus sequence called the PY motif. Mutations in this motif in SCNN1B and SCNN1G are associated with Liddle syndrome, which is characterized by early-onset hypertension [5, 50]. The PY motif is recognized by Nedd4-2 that is a ubiquitin ligase. Thus, mutations in the PY motif reduce ubiquitylation of ENaC leading to the accumulation of ENaC in the membrane, consequently enhance the activity of ENaC [45].ENaC expression in tumorsThe observation that [Na⁺] is higher in many cancerous cells as compared to non-cancerous cells has led to the suggestion that enhanced expression of ENaC may be responsible for increased metastasis [33]. However, analysis of RNA sequencing data of ENaC-encoding genes, and clinical data of cervical cancer patients from The Cancer Genome Atlas showed a negative correlation with histologic grades of tumor [51]. Similarly, studies on breast cancer cells that altered α-ENaC levels by over-expression or siRNA-mediated knockdown showed that increased α-ENaC expression was associated with decreased breast cancer cell proliferation [54]. In contrast, analysis of RNA sequencing data from The Cancer Genome Atlas showed that high expression of SCNN1A was correlated with poor prognosis in patients with ovarian cancer [35]. These findings indicate that the association of ENaC levels with tumorigenesis varies depending on the tissue.COVID-19The surface of SARS-CoV-2 virions that cause COVID-19 is covered by many glycosylated S (spike) proteins. These S proteins bind to the membrane-bound angiotensin-converting enzyme 2 (ACE2) as a first step in the entry of the virion into the host cell. Viral entry into the cell is dependent on the cleavage of the S protein (at Arg-667/Ser-668) by a serine-protease. Anand et al. showed that this cleavage site has a sequence motif that is homologous to the furin cleavage site in α-ENaC [2]. A comprehensive review on the pathological consequences of COVID-19 suggests a role for ENaC in the early phases of COVID-19 infection in the respiratory tract epithelia [17].

Lysophospholipid (S1P) receptors in GtoPdb v.2023.1

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Sphingosine 1-phosphate (S1P) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid receptors [96]) are activated by the endogenous lipid sphingosine 1-phosphate (S1P). Originally cloned as orphan members of the endothelial differentiation gene (edg) family [16, 123], the receptors are currently designated as S1P₁R through S1P₅R [73, 16, 123]. Their gene nomenclature has been codified as human S1PR1, S1PR2, etc. (HUGO Gene Nomenclature Committee, HGNC) and S1pr1, S1pr2, etc. for mice (Mouse Genome Informatics Database, MGI) to reflect species and receptor function. All S1P receptors (S1PRs) have been knocked-out in mice constitutively and in some cases, conditionally.

S1PRs, particularly S1P₁, are expressed throughout all mammalian organ systems. Ligand delivery occurs via two known carriers (or "chaperones"): albumin and HDL-bound apolipoprotein M (ApoM), the latter of which elicits biased agonist signaling by S1P₁ in multiple cell types [18, 53]. The five S1PRs, two chaperones, and active cellular metabolism have complicated analyses of receptor ligand binding in native systems.

Signaling pathways and physiological roles have been characterized through radioligand binding in heterologous expression systems, targeted deletion of the different S1PRs, and most recently, mouse models that report in vivo S1P₁R activation [101, 103]. The structures of S1P₁ [180, 69, 108, 184], S1P₂ [32], S1P₃[116, 187], and S1P₅ [110, 185] are solved, and confirmed aspects of ligand binding, specificity, and receptor activation, determined previously through biochemical and genetic studies [69, 17]. fingolimod (FTY720), the first FDA-approved drug to target any of the lysophospholipid receptors, binds as a phosphorylated metabolite to four of the five S1PRs, and was the first oral therapy for multiple sclerosis (MS) [35]. Second-generation S1PR modulators siponimod, ozanimod, and ponesimod that target S1P₁ and S1P₅ are also FDA approved for the treatment of various MS forms [16, 123]. In 2021, ozanimod became the first S1PR modulator to be FDA approved for the treatment of ulcerative colitis [145]. The mechanisms of action of fingolimod and other S1PR-modulating drugs now in development include binding S1PRs in multiple organ systems, e.g., immune and nervous systems, although the precise nature of their receptor interactions requires clarification [141, 37, 63, 64].

SLC1 family of amino acid transporters in GtoPdb v.2023.1

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The SLC1 family of sodium dependent transporters includes the plasma membrane located glutamate transporters and the neutral amino acid transporters ASCT1 and ASCT2 [3, 52, 39, 40, 9].

SLC6 neurotransmitter transporter family in GtoPdb v.2023.1

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Members of the solute carrier family 6 (SLC6) of sodium- and (sometimes chloride-) dependent neurotransmitter transporters [32, 2, 23, 75] are primarily plasma membrane located and may be divided into four subfamilies that transport monoamines, GABA, glycine and neutral amino acids, plus the related bacterial NSS transporters [109]. The members of this superfamily share a structural motif of 10 TM segments that has been observed in crystal structures of the NSS bacterial homolog LeuT_Aa, a Na⁺-dependent amino acid transporter from Aquiflex aeolicus [137] and in several other transporter families structurally related to LeuT [49].

SLC22 family of organic cation and anion transporters in GtoPdb v.2023.1

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The SLC22 family of transporters is mostly composed of non-selective transporters, which are expressed highly in liver, kidney and intestine, playing a major role in drug disposition. The family may be divided into three subfamilies based on the nature of the substrate transported: organic cations (OCTs), organic anions (OATs) and organic zwiterrion/cations (OCTN). Membrane topology is predicted to contain 12 TM domains with intracellular termini, and an extended extracellular loop at TM 1/2.

SLC25 family of mitochondrial transporters in GtoPdb v.2023.1

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Mitochondrial carriers are nuclear-encoded proteins, which translocate solutes across the inner mitochondrial membrane. Mitochondrial carriers are functional as monomers and have six TM alpha-helices and the termini in the mitochondrial intermembrane space.

ABCA subfamily in GtoPdb v.2023.1

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To date, 12 members of the human ABCA subfamily are identified. They share a high degree of sequence conservation and have been mostly related with lipid trafficking in a wide range of body locations. Mutations in some of these genes have been described to cause severe hereditary diseases related with lipid transport, such as fatal surfactant deficiency or harlequin ichthyosis. In addition, most of them are hypothesized to participate in the subcellular sequestration of drugs, thereby being responsible for the resistance of several carcinoma cell lines against drug treatment [1, 2].

ABCB subfamily in GtoPdb v.2023.1

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The ABCB subfamily is composed of four full transporters and two half transporters. This is the only human subfamily to have both half and full types of transporters. ABCB1 was discovered as a protein overexpressed in certain drug resistant tumor cells. It is expressed primarily in the blood brain barrier and liver and is thought to be involved in protecting cells from toxins. Cells that overexpress this protein exhibit multi-drug resistance [8, 1].

ABCC subfamily in GtoPdb v.2023.1

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Subfamily ABCC contains thirteen members and nine of these transporters are referred to as the Multidrug Resistance Proteins (MRPs). The MRP proteins are found throughout nature and they mediate many important functions. They are known to be involved in ion transport, toxin secretion, and signal transduction [7, 2].

ABCD subfamily of peroxisomal ABC transporters in GtoPdb v.2023.1

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Peroxisomes are indispensable organelles in higher eukaryotes. They are essential for the oxidation of a wide variety of metabolites, which include: saturated, monounsaturated and polyunsaturated fatty acids, branched-chain fatty acids, bile acids and dicarboxylic acids [5]. However, the peroxisomal membrane forms an impermeable barrier to these metabolites. The mammalian peroxisomal membrane harbours three ATP-binding cassette (ABC) half-transporters, named ABCD1, -2 and -3. The ABCD transporters predominantly act as homodimers to transport different acyl-CoAs.

ABCG subfamily in GtoPdb v.2023.1

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This family of 'half-transporters' act as homo- or heterodimers; particularly ABCG5 and ABCG8 are thought to be obligate heterodimers. The ABCG5/ABCG heterodimer sterol transporter structure has been determined [6], suggesting an extensive intracellular nucleotide binding domain linked to the transmembrane domains by a fold in the primary sequence. The functional ABCG2 transporter appears to be a homodimer with structural similarities to the ABCG5/ABCG8 heterodimer [10, 1].

P1B P-type ATPases: Cu⁺-ATPases in GtoPdb v.2023.1

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Copper-transporting ATPases convey copper ions across cell-surface and intracellular membranes. They consist of eight TM domains and associate with multiple copper chaperone proteins (e.g. ATOX1, O00244).

SLC14 family of facilitative urea transporters in GtoPdb v.2023.1

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As a product of protein catabolism, urea is moved around the body and through the kidneys for excretion. Although there is experimental evidence for concentrative urea transporters, these have not been defined at the molecular level. The SLC14 family are facilitative transporters, allowing urea movement down its concentration gradient. Multiple splice variants of these transporters have been identified; for UT-A transporters, in particular, there is evidence for cell-specific expression of these variants with functional impact [6, 1]. Topographical modelling suggests that the majority of the variants of SLC14 transporters have 10 TM domains, with a glycosylated extracellular loop at TM5/6, and intracellular C- and N-termini. The UT-A1 splice variant, exceptionally, has 20 TM domains, equivalent to a combination of the UT-A2 and UT-A3 splice variants.

SLC15 family of peptide transporters in GtoPdb v.2023.1

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The Solute Carrier 15 (SLC15) family of peptide transporters, alias H⁺-coupled oligopeptide cotransporter family, is a group of membrane transporters known for their key role in the cellular uptake of di- and tripeptides (di/tripeptides). Of its members, SLC15A1 (PEPT1) chiefly mediates intestinal absorption of luminal di/tripeptides from overall dietary protein digestion, SLC15A2 (PEPT2) mainly allows renal tubular reuptake of di/tripeptides from ultrafiltration and brain-to-blood efflux of di/tripeptides in the choroid plexus, SLC15A3 (PHT2) and SLC15A4 (PHT1) interact with both di/tripeptides and histidine, e.g. in certain immune cells, and SLC15A5 has unknown physiological function. In addition, the SLC15 family of peptide transporters variably interacts with a very large number of peptidomimetics and peptide-like drugs. It is conceivable, based on the currently acknowledged structural and functional differences, to divide the SLC15 family of peptide transporters into two subfamilies [3].

SLC27 family of fatty acid transporters in GtoPdb v.2023.1

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Fatty acid transporter proteins (FATPs) are a family (SLC27) of six transporters (FATP1-6). They have at least one, and possibly six [6, 13], transmembrane segments, and are predicted on the basis of structural similarities to form dimers. SLC27 members have several structural domains: integral membrane associated domain, peripheral membrane associated domain, FATP signature, intracellular AMP binding motif, dimerization domain, lipocalin motif, and an ER localization domain (identified in FATP4 only) [4, 10, 11]. These transporters are unusual in that they appear to express intrinsic very long-chain acyl-CoA synthetase (EC 6.2.1.- , EC 6.2.1.7) enzyme activity. Within the cell, these transporters may associate with plasma and peroxisomal membranes. FATP1-4 and -6 transport long- and very long-chain fatty acids, while FATP5 transports long-chain fatty acids as well as bile acids [9, 13, 1].

SLC31 family of copper transporters in GtoPdb v.2023.1

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SLC31 family members, alongside the Cu-ATPases are involved in the regulation of cellular copper levels. The CTR1 transporter is a cell-surface transporter to allow monovalent copper accumulation into cells, while CTR2 appears to be a vacuolar/vesicular transporter [5]. Functional copper transporters appear to be trimeric with each subunit having three TM regions and an extracellular N-terminus. CTR1 is considered to be a higher affinity copper transporter compared to CTR2. The stoichiometry of copper accumulation is unclear, but appears to be energy-independent [4].

SLC36 family of proton-coupled amino acid transporters in GtoPdb v.2023.1

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Members of the SLC36 family of proton-coupled amino acid transporters are involved in membrane transport of amino acids and derivatives [29, 30]. The four transporters show variable tissue expression patterns and are expressed in various cell types at the plasma-membrane and in intracellular organelles. PAT1 is expressed at the luminal surface of the small intestine and absorbs amino acids and derivatives [4]. In lysosomes, PAT1 functions as an efflux mechanism for amino acids produced during intralysosomal proteolysis [2, 26]. PAT2 is expressed at the apical membrane of the renal proximal tubule [7] and at the plasma-membrane in brown/beige adipocytes [31]. PAT1 and PAT4 are involved in regulation of the mTORC1 pathway [12, 28]. More comprehensive lists of substrates can be found within the reviews under Further Reading and in the references [3].

SLC39 family of metal ion transporters in GtoPdb v.2023.1

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Along with the SLC30 family, SLC39 family members regulate zinc movement in cells. SLC39 metal ion transporters accumulate zinc into the cytosol. Membrane topology modelling suggests the presence of eight TM regions with both termini extracellular or in the lumen of intracellular organelles. The mechanism for zinc transport for many members is unknown but appears to involve co-transport of bicarbonate ions [3, 4].

SLC47 family of multidrug and toxin extrusion transporters in GtoPdb v.2023.1

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Human multidrug and toxin extrusion MATE1 and MATE2-K are H⁺/organic cation antiporters [1]. They are predominantly expressed in the kidney and play a role in renal tubular secretion of cationic drugs.

SLCO family of organic anion transporting polypeptides in GtoPdb v.2023.1

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The SLCO superfamily is comprised of the organic anion transporting polypeptides (OATPs). The 11 human OATPs are divided into 6 families and ten subfamilies based on amino acid identity. These proteins are located on the plasma membrane of cells throughout the body. They have 12 TM domains and intracellular termini, with multiple putative glycosylation sites. OATPs mediate the sodium-independent uptake of a wide range of amphiphilic substrates, including many drugs and toxins. Due to the multispecificity of these proteins, this guide lists classes of substrates and inhibitors for each family member. More comprehensive lists of substrates, inhibitors, and their relative affinities may be found in the review articles listed below.

Cytochrome P450 in GtoPdb v.2023.1

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The cytochrome P450 enzyme superfamily (CYP), E.C. 1.14.-.-, are haem-containing monooxygenases with a vast range of both endogenous and exogenous substrates. These include sterols, fatty acids, eicosanoids, fat-soluble vitamins, hormones, pesticides and carcinogens as well as drugs. Listed below are the human enzymes, their relationship with rodent CYP enzyme activities is obscure in that the species orthologue may not metabolise the same substrates. Some of the CYP enzymes located in the liver are particularly important for drug metabolism, both hepatic and extrahepatic CYP enzymes also contribute to patho/physiological processes. Genetic variation of CYP isoforms is widespread and likely underlies a proportion of individual variation in drug disposition. The superfamily has the root symbol CYP, followed by a number to indicate the family, a capital letter for the subfamily with a numeral for the individual enzyme. Some CYP are able to metabolise multiple substrates, others are oligo- or mono- specific. CYP also catalyse diverse oxidation and reduction reactions. These include ring hydroxylation, N-oxidation, sulfoxidation, epoxidation, the dealkylation of N-, S- and O- moieties, desulfation, deamination, as well as reduction of azo, nitro and N-oxide groups.

Eicosanoid turnover in GtoPdb v.2023.1

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Eicosanoids are 20-carbon fatty acids, where the usual focus is the polyunsaturated analogue arachidonic acid and its metabolites. Arachidonic acid is thought primarily to derive from phospholipase A2 action on membrane phosphatidylcholine, and may be re-cycled to form phospholipid through conjugation with coenzyme A and subsequently glycerol derivatives. Oxidative metabolism of arachidonic acid is conducted through three major enzymatic routes: cyclooxygenases; lipoxygenases and cytochrome P450-like epoxygenases, particularly CYP2J2. Isoprostanes are structural analogues of the prostanoids (hence the nomenclature D-, E-, F-isoprostanes and isothromboxanes), which are produced in the presence of elevated free radicals in a non-enzymatic manner, leading to suggestions for their use as biomarkers of oxidative stress. Molecular targets for their action have yet to be defined.

Adenosine turnover in GtoPdb v.2023.1

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A multifunctional, ubiquitous molecule, adenosine acts at cell-surface G protein-coupled receptors, as well as numerous enzymes, including protein kinases and adenylyl cyclase. Extracellular adenosine is thought to be produced either by export or by metabolism, predominantly through ecto-5’-nucleotidase activity (also producing inorganic phosphate). It is inactivated either by extracellular metabolism via adenosine deaminase (also producing ammonia) or, following uptake by nucleoside transporters, via adenosine deaminase or adenosine kinase (requiring ATP as co-substrate). Intracellular adenosine may be produced by cytosolic 5’-nucleotidases or through S-adenosylhomocysteine hydrolase (also producing L-homocysteine).

Nitric oxide synthases in GtoPdb v.2023.1

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Nitric oxide synthases (NOS, E.C. 1.14.13.39) are a family of oxidoreductases that synthesize nitric oxide (NO.) via the NADPH and oxygen-dependent consumption of L-arginine with the resultant by-product, L-citrulline. There are 3 NOS isoforms and they are related by their capacity to produce NO, highly conserved organization of functional domains and significant homology at the amino acid level. NOS isoforms are functionally distinguished by the cell type where they are expressed, intracellular targeting and transcriptional and post-translation mechanisms regulating enzyme activity. The nomenclature suggested by NC-IUPHAR of NOS I, II and III [12] has not gained wide acceptance, and the 3 isoforms are more commonly referred to as neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS) which reflect the location of expression (nNOS and eNOS) and inducible expression (iNOS). All are dimeric enzymes that shuttle electrons from NADPH, which binds to a C-terminal reductase domain, through the flavins FAD and FMN to the oxygenase domain of the other monomer to enable the BH4-dependent reduction of heme bound oxygen for insertion into the substrate, L-arginine. Electron flow from reductase to oxygenase domain is controlled by calmodulin binding to canonical calmodulin binding motif located between these domains. eNOS and nNOS isoforms are activated at concentrations of calcium greater than 100 nM, while iNOS shows higher affinity for Ca²⁺/calmodulin with great avidity and is essentially calcium-independent and constitutively active. Efficient stimulus-dependent coupling of nNOS and eNOS is achieved via subcellular targeting through respective N-terminal PDZ and fatty acid acylation domains whereas iNOS is largely cytosolic and function is independent of intracellular location. nNOS is primarily expressed in the brain and neuronal tissue, iNOS in immune cells such as macrophages and eNOS in the endothelial layer of the vasculature although exceptions in other cells have been documented. L-NAME and related modified arginine analogues are inhibitors of all three isoforms, with IC₅₀ values in the micromolar range.

Adenylyl cyclases (ACs) in GtoPdb v.2023.1

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Adenylyl cyclase, E.C. 4.6.1.1, converts ATP to cyclic AMP and pyrophosphate. Mammalian membrane-delimited adenylyl cyclases (nomenclature as approved by the NC-IUPHAR Subcommittee on Adenylyl cyclases [11]) are typically made up of two clusters of six TM domains separating two intracellular, overlapping catalytic domains that are the target for the nonselective activators Gα_s (the stimulatory G protein α subunit) and forskolin (except AC9, [28]). adenosine and its derivatives (e.g. 2',5'-dideoxyadenosine), acting through the P-site,are inhibitors of adenylyl cyclase activity [35]. Four families of membranous adenylyl cyclase are distinguishable: calmodulin-stimulated (AC1, AC3 and AC8), Ca²⁺- and Gβγ-inhibitable (AC5, AC6 and AC9), Gβγ-stimulated and Ca²⁺-insensitive (AC2, AC4 and AC7), and forskolin-insensitive (AC9) forms. A soluble adenylyl cyclase (AC10) lacks membrane spanning regions and is insensitive to G proteins.It functions as a cytoplasmic bicarbonate (pH-insensitive) sensor [7].

Phosphodiesterases, 3',5'-cyclic nucleotide (PDEs) in GtoPdb v.2023.1

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3',5'-Cyclic nucleotide phosphodiesterases (PDEs, 3',5'-cyclic-nucleotide 5'-nucleotidohydrolase), E.C. 3.1.4.17, catalyse the hydrolysis of a 3',5'-cyclic nucleotide (usually cyclic AMP or cyclic GMP). isobutylmethylxanthine is a nonselective inhibitor with an IC₅₀ value in the millimolar range for all isoforms except PDE 8A, 8B and 9A. A 2',3'-cyclic nucleotide 3'-phosphodiesterase (E.C. 3.1.4.37 CNPase) activity is associated with myelin formation in the development of the CNS.

Cyclooxygenase in GtoPdb v.2023.1

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Prostaglandin (PG) G/H synthase, most commonly referred to as cyclooxygenase (COX, (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate,hydrogen-donor : oxygen oxidoreductase) activity, catalyses the formation of PGG₂ from arachidonic acid. Hydroperoxidase activity inherent in the enzyme catalyses the formation of PGH₂ from PGG₂. COX-1 and -2 can be nonselectively inhibited by ibuprofen, ketoprofen, naproxen, indomethacin and paracetamol (acetaminophen). PGH₂ may then be metabolised to prostaglandins and thromboxanes by various prostaglandin synthases in an apparently tissue-dependent manner.

Haem oxygenase in GtoPdb v.2023.1

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Haem oxygenase (heme,hydrogen-donor:oxygen oxidoreductase (α-methene-oxidizing, hydroxylating)), E.C. 1.14.99.3, converts heme into biliverdin and carbon monoxide, utilizing NADPH as cofactor.

Hydrogen sulphide synthesis in GtoPdb v.2023.1

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Hydrogen sulfide is a gasotransmitter, with similarities to nitric oxide and carbon monoxide. Although the enzymes indicated below have multiple enzymatic activities, the focus here is the generation of hydrogen sulphide (H₂S) and the enzymatic characteristics are described accordingly. Cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) are pyridoxal phosphate (PLP)-dependent enzymes. 3-mercaptopyruvate sulfurtransferase (3-MPST) functions to generate H₂S; only CAT is PLP-dependent, while 3-MPST is not. Thus, this third pathway is sometimes referred to as PLP-independent. CBS and CSE are predominantly cytosolic enzymes, while 3-MPST is found both in the cytosol and the mitochondria. For an authoritative review on the pharmacological modulation of H₂S levels, see Szabo and Papapetropoulos, 2017 [8].

Pattern recognition receptors in GtoPdb v.2023.1

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Pattern Recognition Receptors (PRRs, [110]) (nomenclature as agreed by NC-IUPHAR sub-committee on Pattern Recognition Receptors, [20]) participate in the innate immune response to microbial agents, the stimulation of which leads to activation of intracellular enzymes and regulation of gene transcription. PRRs express multiple leucine-rich regions to bind a range of microbially-derived ligands, termed PAMPs or pathogen-associated molecular patterns or endogenous ligands, termed DAMPS or damage-associated molecular patterns. These include peptides, carbohydrates, peptidoglycans, lipoproteins, lipopolysaccharides, and nucleic acids. PRRs include both cell-surface and intracellular proteins. PRRs may be divided into signalling-associated members, identified here, and endocytic members, the function of which appears to be to recognise particular microbial motifs for subsequent cell attachment, internalisation and destruction. Some are involved in inflammasome formation, and modulation of IL-1β cleavage and secretion, and others in the initiation of the type I interferon response.

PRRs included in the Guide To PHARMACOLOGY are:

Catalytic PRRs (see links below this overview)
Toll-like receptors (TLRs)
Nucleotide-binding oligomerization domain, leucine-rich repeat containing receptors (NLRs, also known as NOD (Nucleotide oligomerisation domain)-like receptors)
RIG-I-like receptors (RLRs)
Caspase 4 and caspase 5

Non-catalytic PRRs
Absent in melanoma (AIM)-like receptors (ALRs)
C-type lectin-like receptors (CLRs)
Other pattern recognition receptors
Advanced glycosylation end-product specific receptor (RAGE)

Tumour necrosis factor (TNF) receptor family in GtoPdb v.2023.1

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Dysregulated TNFR signalling is associated with many inflammatory disorders, including some forms of arthritis and inflammatory bowel disease, and targeting TNF has been an effective therapeutic strategy in these diseases and for cancer immunotherapy [5, 6, 49].

SLC51 family of steroid-derived molecule transporters in GtoPdb v.2023.1

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The SLC51 organic solute transporter family of transporters is a pair of heterodimeric proteins which regulate bile salt movements in the small intestine, bile duct, and liver, as part of the enterohepatic circulation [2, 5, 1]. OSTα/OSTβ is also expressed in steroidogenic cells of the brain and adrenal gland, where it may contribute to steroid sulphate movement [6]. Bile acid and steroid sulphate transport is suggested to be facilitative and independent of sodium, potassium, chloride ions or protons [5, 2]. OSTα/OSTβ heterodimers have been shown to transport [³H]taurocholic acid, [³H]dehydroepiandrosterone sulphate, [³H]estrone-3-sulphate, [³H]pregnenolone sulphate and [³H]dehydroepiandrosterone sulphate[2, 5, 6]. OSTα/OSTβ-mediated transport is inhibited by clofazimine and fidaxomicin [9, 11]. OSTα is suggested to be a seven TM protein, while OSTβ is a single TM 'ancillary' protein, both of which are thought to have intracellular C-termini [8]. Both proteins function in solute transport [8, 4]. Inherited mutations in OSTα and OSTβ are associated with liver disease and congenital diarrhea in children [10, 7].

Chemerin receptors in GtoPdb v.2023.1

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Nomenclature for the chemerin receptors is presented as recommended by NC-IUPHAR [15, 44]). The chemoattractant protein and adipokine, chemerin, has been shown to be the endogenous ligand for both chemerin family receptors. Chemerin₁ was the founding family member, and when GPR1 was de-orphanised it was re-named Chermerin₂ [44]. Chemerin₁ is also activated by the lipid-derived, anti-inflammatory ligand resolvin E1 (RvE1), which is formed via the sequential metabolism of EPA by aspirin-modified cyclooxygenase and lipoxygenase [2, 3]. In addition, two GPCRs for resolvin D1 (RvD1) have been identified: FPR2/ALX, the lipoxin A₄ receptor, and GPR32, an orphan receptor [46].

Succinate receptor in GtoPdb v.2023.1

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Nomenclature as recommended by NC-IUPHAR [8]. The succinate receptor (GPR91, SUCNR1) is activated by the tricarboxylic acid (or Krebs) cycle intermediate succinate and other dicarboxylic acids with less clear physiological relevance such as maleate [17]. Since its pairing with its endogenous ligand in 2004, intense research has focused on the receptor-ligand pair role in various (patho)physiological processes such as regulation of renin production [17, 39], ischemia injury [17], fibrosis [25], retinal angiogenesis [34], inflammation [25, 23], immune response [32], obesity [44, 26, 21], diabetes [42, 22, 39], platelet aggregation [38, 36] or cancer [28, 46]. The succinate receptor is coupled to G_i/o [11, 17] and G_q/11 protein families [31, 17, 40]. Although the receptor is, upon ligand addition, rapidly desensitized [19, 31], and in some cells internalized [17], it seems to recruit arrestins weakly [10]. The cellular activation of the succinate receptor triggers various signalling pathways such as decrease of cAMP levels, [Ca²⁺]ⁱ mobilization and activation of kinases (ERK, c-Jun, Akt, Src, p38, PI3Kβ, etc.) [12]. The receptor is broadly expressed but is notably abundant in immune cells (M2 macrophages [40, 21], monocytes [32], immature dendritic cells [32], adipocytes [44], platelets [38, 36], etc.) and in the kidney [17].

Oxoglutarate receptor in GtoPdb v.2023.1

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Nomenclature as recommended by NC-IUPHAR [3].

Delta subfamily in GtoPdb v.2023.1

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PKCδ and PKCθ are PKC isoforms that are activated by diacylglycerol and may be inhibited by calphostin C, Gö 6983 and chelerythrine.

Phosphatidylinositol-4,5-bisphosphate 3-kinase family in GtoPdb v.2023.1

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PI3K activation is one of the most important signal transduction pathways used to transmit signals from cell-surface receptors to regulate intracellular processes (cell growth, survival, proliferation and movement). PI3K catalytic (and regulatory) subunits play vital roles in normal cell function and in disease. Progress made in developing PI3K-targeted agents as potential therapeutics for treating cancer and other diseases is reviewed by Fruman et al. (2017) [41].

Integrins in GtoPdb v.2023.1

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Integrins are unusual signalling proteins that function to signal both from the extracellular environment into the cell, but also from the cytoplasm to the external of the cell. The intracellular signalling cascades associated with integrin activation focus on protein kinase activities, such as focal adhesion kinase and Src. Based on this association between extracellular signals and intracellular protein kinase activity, we have chosen to include integrins in the 'Catalytic receptors' section of the database until more stringent criteria from NC-IUPHAR allows precise definition of their classification.

Integrins are heterodimeric entities, composed of α and β subunits, each 1TM proteins, which bind components of the extracellular matrix or counter-receptors expressed on other cells. One class of integrin contains an inserted domain (I) in its α subunit, and if present (in α1, α2, α10, α11, αD, αE, αL, αM and αX), this I domain contains the ligand binding site. All β subunits possess a similar I-like domain, which has the capacity to bind ligand, often recognising the RGD motif. The presence of an α subunit I domain precludes ligand binding through the β subunit. Integrins provide a link between ligand and the actin cytoskeleton (through typically short intracellular domains). Integrins bind several divalent cations, including a Mg²⁺ ion in the I or I-like domain that is essential for ligand binding. Other cation binding sites may regulate integrin activity or stabilise the 3D structure. Integrins regulate the activity of particular protein kinases, including focal adhesion kinase and integrin-linked kinase. Cellular activation regulates integrin ligand affinity via inside-out signalling and ligand binding to integrins can regulate cellular activity via outside-in signalling.

Several drugs that target integrins are in clinical use including: (1) abciximab (αIIbβ3) for short term prevention of coronary thrombosis, (2) vedolizumab (α4β7) to reduce gastrointestinal inflammation, and (3) natalizumab (α4β1) in some cases of severe multiple sclerosis.

Ceramide turnover in GtoPdb v.2023.1

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Ceramides are a family of sphingophospholipids synthesized in the endoplasmic reticulum, which mediate cell stress responses, including apoptosis, autophagy and senescence, Serine palmitoyltransferase generates 3-ketosphinganine, which is reduced to dihydrosphingosine. N-Acylation allows the formation of dihydroceramides, which are subsequently reduced to form ceramides. Once synthesized, ceramides are trafficked from the ER to the Golgi bound to the ceramide transfer protein, CERT (COL4A3BP, Q9Y5P4). Ceramide can be metabolized via multiple routes, ensuring tight regulation of its cellular levels. Addition of phosphocholine generates sphingomyelin while carbohydrate is added to form glucosyl- or galactosylceramides. Ceramidase re-forms sphingosine or sphinganine from ceramide or dihydroceramide. Phosphorylation of ceramide generates ceramide phosphate. The determination of accurate kinetic parameters for many of the enzymes in the sphingolipid metabolic pathway is complicated by the lipophilic nature of the substrates.

Sphingosine 1-phosphate turnover in GtoPdb v.2023.1

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S1P (sphingosine 1-phosphate) is a bioactive lipid which, after release from cells via certain transporters, acts as a ligand for a family of five S1P-specific G protein-coupled receptors (S1P1-5). However, it also has a number of intracellular targets. S1P is formed by the ATP-dependent phosphorylation of sphingosine, catalysed by two isoforms of sphingosine kinase (EC 2.7.1.91). It can be dephosphorylated back to sphingosine by sphingosine 1-phosphate phosphatase (EC 3.1.3) or cleaved into phosphoethanolamine and hexadecenal by sphingosine 1-phosphate lyase (EC 4.1.2.27). Recessive mutations in the S1P lyase (SPL) gene underlie a recently identified sphingolipidosis: SPL Insufficiency Syndrome (SPLIS). In general, S1P promotes cell survival, proliferation, migration, adhesion and inhibition of apoptosis. Intracellular S1P affects epigenetic regulation, endosomal processing, mitochondrial function and cell proliferation/senescence. S1P has myriad physiological functions, including vascular development, lymphocyte trafficking and neurogenesis. However, S1P is also involved in a number of diseases such as cancer, inflammation and fibrosis. Therefore, its GPCRs and enzymes of synthesis and degradation are a major focus for drug discovery.

Phosphatidylinositol kinases in GtoPdb v.2023.1

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Phosphatidylinositol may be phosphorylated at either 3- or 4- positions on the inositol ring by PI 3-kinases or PI 4-kinases, respectively.

Phosphatidylinositol 3-kinases

Phosphatidylinositol 3-kinases (PI3K, provisional nomenclature) catalyse the introduction of a phosphate into the 3-position of phosphatidylinositol (PI), phosphatidylinositol 4-phosphate (PIP) or phosphatidylinositol 4,5-bisphosphate (PIP₂). There is evidence that PI3K can also phosphorylate serine/threonine residues on proteins. In addition to the classes described below, further serine/threonine protein kinases, including ATM (Q13315) and mTOR (P42345), have been described to phosphorylate phosphatidylinositol and have been termed PI3K-related kinases. Structurally, PI3Ks have common motifs of at least one C2, calcium-binding domain and helical domains, alongside structurally-conserved catalytic domains. wortmannin and LY 294002 are widely-used inhibitors of PI3K activities. wortmannin is irreversible and shows modest selectivity between Class I and Class II PI3K, while LY294002 is reversible and selective for Class I compared to Class II PI3K.

Class I PI3Ks (EC 2.7.1.153) phosphorylate phosphatidylinositol 4,5-bisphosphate to generate phosphatidylinositol 3,4,5-trisphosphate and are heterodimeric, matching catalytic and regulatory subunits. Class IA PI3Ks include p110α, p110β and p110δ catalytic subunits, with predominantly p85 and p55 regulatory subunits. The single catalytic subunit that forms Class IB PI3K is p110γ. Class IA PI3Ks are more associated with receptor tyrosine kinase pathways, while the Class IB PI3K is linked more with GPCR signalling.

Class II PI3Ks (EC 2.7.1.154) phosphorylate phosphatidylinositol to generate phosphatidylinositol 3-phosphate (and possibly phosphatidylinositol 4-phosphate to generate phosphatidylinositol 3,4-bisphosphate). Three monomeric members exist, PI3K-C2α, β and β, and include Ras-binding, Phox homology and two C2 domains.

The only class III PI3K isoform (EC 2.7.1.137) is a heterodimer formed of a catalytic subunit (VPS34) and regulatory subunit (VPS15).

Phosphatidylinositol 4-kinases

Phosphatidylinositol 4-kinases (EC 2.7.1.67) generate phosphatidylinositol 4-phosphate and may be divided into higher molecular weight type III and lower molecular weight type II forms.

Hydrolases in GtoPdb v.2023.1

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Listed in this section are hydrolases not accumulated in other parts of the Concise Guide, such as monoacylglycerol lipase and acetylcholinesterase. Pancreatic lipase is the predominant mechanism of fat digestion in the alimentary system; its inhibition is associated with decreased fat absorption. CES1 is present at lower levels in the gut than CES2 (P23141), but predominates in the liver, where it is responsible for the hydrolysis of many aliphatic, aromatic and steroid esters. Hormone-sensitive lipase is also a relatively non-selective esterase associated with steroid ester hydrolysis and triglyceride metabolism, particularly in adipose tissue. Endothelial lipase is secreted from endothelial cells and regulates circulating cholesterol in high density lipoproteins.

Peptidyl-prolyl cis/trans isomerases in GtoPdb v.2023.1

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Peptidyl-prolyl cis/trans isomerases (PPIases) are an enzyme family which catalyse the cis/trans isomerisation of proline peptide bonds to promote the folding and re-folding of peptides and proteins. Three subfamilies have been identified: cyclophilins, FK506-binding proteins and parvulins. Individual PPIases are overexpressed in a number of cancers [62], and family members have been targetted for immunosuppressant effects.

Blood coagulation components in GtoPdb v.2023.1

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Coagulation as a process is interpreted as a mechanism for reducing excessive blood loss through the generation of a gel-like clot local to the site of injury. The process involves the activation, adhesion (see Integrins), degranulation and aggregation of platelets, as well as proteins circulating in the plasma. The coagulation cascade involves multiple proteins being converted to more active forms from less active precursors (for example, prothrombin [Factor II] is converted to thrombin [Factor IIa]), typically through proteolysis (see Proteases). Listed here are the components of the coagulation cascade targeted by agents in current clinical usage or at an advanced level of development.

3.6.5.2 Small monomeric GTPases in GtoPdb v.2023.1

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Small G-proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G-protein found in the cytosol that are homologous to the alpha subunit of heterotrimeric G-proteins, but unlike the alpha subunit of G proteins, a small GTPase can function independently as a hydrolase enzyme to bind to and hydrolyze a guanosine triphosphate (GTP) to form guanosine diphosphate (GDP). The best-known members are the Ras GTPases and hence they are sometimes called Ras subfamily GTPases.

S33: Prolyl aminopeptidase in GtoPdb v.2023.1

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Peptidase family S33 contains mainly exopeptidases that act at the N-terminus of peptides.

Endocannabinoid turnover in GtoPdb v.2023.1

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The principle endocannabinoids are 2-acylglycerol esters, such as 2-arachidonoylglycerol (2-AG), and N-acylethanolamines, such as anandamide (N-arachidonoylethanolamine, AEA). The glycerol esters and ethanolamides are synthesised and hydrolysed by parallel, independent pathways. Mechanisms for release and re-uptake of endocannabinoids are unclear, although potent and selective inhibitors of facilitated diffusion of endocannabinoids across cell membranes have been developed [29]. FABP5 (Q01469) has been suggested to act as a canonical intracellular endocannabinoid transporter in vivo [17]. For the generation of 2-arachidonoylglycerol, the key enzyme involved is diacylglycerol lipase (DAGL), whilst several routes for anandamide synthesis have been described, the best characterized of which involves N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD, [75]). A transacylation enzyme which forms N-acylphosphatidylethanolamines has been identified as a cytosolic enzyme, PLA2G4E (Q3MJ16) [66]. In vitro experiments indicate that the endocannabinoids are also substrates for oxidative metabolism via cyclooxygenase, lipoxygenase and cytochrome P450 enzyme activities [5, 24, 77].

SLC54 Mitochondrial pyruvate carriers in GtoPdb v.2023.1

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Pyruvate is oxidized to acetyl‐CoA by pyruvate dehydrogenase which is localized in the mitochondrial matrix. The mitochondrial pyruvate carrier (MPC) is composed of SLC54 family members (MPC1 and MPC2) [1, 5], which form functional hetero-dimers [9, 8]. The MPC is expressed in the inner mitochondrial membrane and involved in the import of pyruvate into mitochondria [1, 5]. Ubiquitous disruption of either MPC1 or MPC2 expression results in embryonic lethality [11, 12]. Clinically relevant concentrations of the insulin sensitizers, thiazolidinediones, inhibit the MPC [3]. Other clinically relevant inhibitors of the MPC complex are lonidamine [7, 8], quinolone antibacterials [6], entacapone and nitrofurantoin [8].

Receptor guanylyl cyclase (RGC) family in GtoPdb v.2023.1

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The mammalian genome encodes seven guanylyl cyclases, GC-A to GC-G, that are homodimeric transmembrane receptors activated by a diverse range of endogenous ligands. These enzymes convert guanosine-5'-triphosphate to the intracellular second messenger cyclic guanosine-3',5'-monophosphate (cyclic GMP). GC-A, GC-B and GC-C are expressed predominantly in the cardiovascular system, skeletal system and intestinal epithelium, respectively. GC-D and GC-G are found in the olfactory neuropepithelium and Grueneberg ganglion of rodents, respectively. GC-E and GC-F are expressed in retinal photoreceptors.

E3 ubiquitin ligase components in GtoPdb v.2023.1

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Ubiquitination (a.k.a. ubiquitylation) is a protein post-translational modification that typically requires the sequential action of three enzymes: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin ligases) [30]. Ubiquitination of proteins can target them for proteasomal degradation, or modulate cellular processes including cell cycle progression, transcriptional regulation, DNA repair and signal transduction.
E3 ubiquitin ligases, of which there are >600 in humans, are a family of highly heterogeneous proteins and protein complexes that recruit ubiquitin-loaded E2 enzymes to mediate transfer of the ubiquitin molecule from the E2 to protein substrates. Target substrate specificity is determined by a substrate recognition subunit within the E3 complex.
E3 ligases are being exploited as pharmacological targets to facilitate targeted protein degradation (TPD), as an alternative to small molecule inhibitors [3], through the development of proteolysis targeting chimeras (PROTACs) and molecular glues.

Coronavirus (CoV) proteins in GtoPdb v.2023.1

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Coronaviruses are large, often spherical, enveloped, single-stranded positive-sense RNA viruses, ranging in size from 80-220 nm. Their genomes and protein structures are highly conserved. Three coronaviruses have emerged over the last 20 years as serious human pathogens: SARS-CoV was identified as the causative agent in an outbreak in 2002-2003, Middle East respiratory syndrome (MERS) CoV emerged in 2012 and the novel coronavirus SARS-CoV-2 emerged in 2019-2020. SARS-CoV-2 is the virus responsible for the infectious disease termed COVID-19 (WHO Technical Guidance 2020).

SLC66 Lysosomal amino acid transporters in GtoPdb v.2023.1

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This is a family of 5 evolutionarily related proteins. Their structural similarities suggest that they are transporters. Biochemical evidence supports transporter activity for SLC66A1 (LAAT1) and SLC66A4 (CTNS; Cystinosin), primarily exporting amino acids from the lysosome to the cytoplasm. The functions of the 3 remaining members of the family are undetermined.

IUPHAR/BPS Guide to Pharmacology CITE

5-Hydroxytryptamine receptors in GtoPdb v.2023.1

Acetylcholine receptors (muscarinic) in GtoPdb v.2023.1

Adenosine receptors in GtoPdb v.2023.1

Adrenoceptors in GtoPdb v.2023.1

Complement peptide receptors in GtoPdb v.2023.1

Angiotensin receptors in GtoPdb v.2023.1

Apelin receptor in GtoPdb v.2023.1

Bile acid receptor in GtoPdb v.2023.1

Bombesin receptors in GtoPdb v.2023.1

Bradykinin receptors in GtoPdb v.2023.1

Calcitonin receptors in GtoPdb v.2023.1

Calcium-sensing receptor in GtoPdb v.2023.1

Cannabinoid receptors in GtoPdb v.2023.1

Chemokine receptors in GtoPdb v.2023.1

Cholecystokinin receptors in GtoPdb v.2023.1

Class A Orphans in GtoPdb v.2023.1

Adhesion Class GPCRs in GtoPdb v.2023.1

Class C Orphans in GtoPdb v.2023.1

Corticotropin-releasing factor receptors in GtoPdb v.2023.1

Dopamine receptors in GtoPdb v.2023.1

Endothelin receptors in GtoPdb v.2023.1

G protein-coupled estrogen receptor in GtoPdb v.2023.1

Free fatty acid receptors in GtoPdb v.2023.1

Class Frizzled GPCRs in GtoPdb v.2023.1

Ghrelin receptor in GtoPdb v.2023.1

Glucagon receptor family in GtoPdb v.2023.1

Glycoprotein hormone receptors in GtoPdb v.2023.1

Gonadotrophin-releasing hormone receptors in GtoPdb v.2023.1

Histamine receptors in GtoPdb v.2023.1

Kisspeptin receptor in GtoPdb v.2023.1

Leukotriene receptors in GtoPdb v.2023.1

Lysophospholipid (LPA) receptors in GtoPdb v.2023.1

Melanin-concentrating hormone receptors in GtoPdb v.2023.1

Melanocortin receptors in GtoPdb v.2023.1

Melatonin receptors in GtoPdb v.2023.1

Metabotropic glutamate receptors in GtoPdb v.2023.1

Motilin receptor in GtoPdb v.2023.1

Neuromedin U receptors in GtoPdb v.2023.1

Neuropeptide FF/neuropeptide AF receptors in GtoPdb v.2023.1

Neuropeptide S receptor in GtoPdb v.2023.1

Neuropeptide W/neuropeptide B receptors in GtoPdb v.2023.1

Neuropeptide Y receptors in GtoPdb v.2023.1

Neurotensin receptors in GtoPdb v.2023.1

Hydroxycarboxylic acid receptors in GtoPdb v.2023.1

Opioid receptors in GtoPdb v.2023.1

Orexin receptors in GtoPdb v.2023.1

P2Y receptors in GtoPdb v.2023.1

Parathyroid hormone receptors in GtoPdb v.2023.1

QRFP receptor in GtoPdb v.2023.1

Platelet-activating factor receptor in GtoPdb v.2023.1

Prokineticin receptors in GtoPdb v.2023.1

Prostanoid receptors in GtoPdb v.2023.1

Proteinase-activated receptors in GtoPdb v.2023.1

Relaxin family peptide receptors in GtoPdb v.2023.1

Somatostatin receptors in GtoPdb v.2023.1

Tachykinin receptors in GtoPdb v.2023.1

Thyrotropin-releasing hormone receptors in GtoPdb v.2023.1

Trace amine receptor in GtoPdb v.2023.1

Urotensin receptor in GtoPdb v.2023.1

Vasopressin and oxytocin receptors in GtoPdb v.2023.1

VIP and PACAP receptors in GtoPdb v.2023.1

Calcium- and sodium-activated potassium channels (KCa, KNa) in GtoPdb v.2023.1

Cyclic nucleotide-regulated channels (CNG) in GtoPdb v.2023.1

GABAA receptors in GtoPdb v.2023.1

Glycine receptors in GtoPdb v.2023.1

Inwardly rectifying potassium channels (KIR) in GtoPdb v.2023.1

Ionotropic glutamate receptors in GtoPdb v.2023.1

P2X receptors in GtoPdb v.2023.1

Transient Receptor Potential channels (TRP) in GtoPdb v.2023.1

Two-pore domain potassium channels (K2P) in GtoPdb v.2023.1

Voltage-gated calcium channels (CaV) in GtoPdb v.2023.1

Voltage-gated potassium channels (Kv) in GtoPdb v.2023.1

Voltage-gated sodium channels (NaV) in GtoPdb v.2023.1

ZAC in GtoPdb v.2023.1

1A. Thyroid hormone receptors in GtoPdb v.2023.1

1F. Retinoic acid-related orphans in GtoPdb v.2023.1

1H. Liver X receptor-like receptors in GtoPdb v.2023.1

1I. Vitamin D receptor-like receptors in GtoPdb v.2023.1

2A. Hepatocyte nuclear factor-4 receptors in GtoPdb v.2023.1

Calcium- and sodium-activated potassium channels (K_Ca, K_Na) in GtoPdb v.2023.1

GABA_A receptors in GtoPdb v.2023.1

Inwardly rectifying potassium channels (K_IR) in GtoPdb v.2023.1

Two-pore domain potassium channels (K_2P) in GtoPdb v.2023.1

Voltage-gated calcium channels (Ca_V) in GtoPdb v.2023.1

Voltage-gated potassium channels (K_v) in GtoPdb v.2023.1

Voltage-gated sodium channels (Na_V) in GtoPdb v.2023.1

P1B P-type ATPases: Cu⁺-ATPases in GtoPdb v.2023.1