This journal is designed to house citation summaries for contributions to the IUPHAR/BPS Guide to Pharmacology (GtoPdb) database. The journal is not open to general submissions, only curators of the GtoPdb can submit to the journal. The citation summaries exist as an adjunct to the database to facilitate the recognition of citations to and from the database by citation analysers.
PIEZO proteins are the pore-forming subunits of trimeric ion channels that open rapidly in response to mechanical stimuli such as membrane stretch, allowing positively charged ions such as the calcium ion to flow into the cell to change cellular structure and function. The proteins are eukaryotic, not prokaryotic, and lack sequence or structural homology to other proteins. There are two main types: In humans, there is PIEZO1 of 2521 amino acids and PIEZO2 of 2752 amino acids, which can form homomeric PIEZO1 and PIEZO2 channels. Membrane stretching causes complex changes in the channels that include a reduced inward curvature, an expansion of the N-terminal transmembrane helical units and an opening of the central ion pore region comprising the last two C-terminal helices. When there is sustained membrane stretching, the channels may adapt by inactivating at various rates depending on the cell type and context. There are many roles of the channels in diverse organ systems including cardiovascular, gastrointestinal, haematological, hepatobiliary, immune, integumental, musculoskeletal, neuronal, reproductive, respiratory and urinary systems as well as adipose tissue and cancers. The expression and functions of PIEZO1 are broad and diverse across many cell types and organs, whereas PIEZO2 is more restricted.
GtoPdb_general: generated Thu Dec 11 12:34:39 2025; family F967, Piezo channels; version 2025.4.
Copyright (c) 2025 The authors http://creativecommons.org/licenses/by-sa/4.0
3.6.5.2 Small monomeric GTPases in GtoPdb v.2025.4
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.
GtoPdb_general: generated Thu Dec 11 12:34:39 2025; family F896, 3.6.5.2 Small monomeric GTPases; version 2025.4.
Orai channels are pore forming proteins which underlie calcium release-activated calcium (CRAC) channels. In numerous cell types, calcium influx is predominantly governed by store-operated calcium channels (SOCs). The process of store-operated calcium entry (SOCE) is orchestrated through the concerted interaction of two essential molecular components: the pore-forming Orai proteins (Orai1-3) and the endoplasmic reticulum calcium-sensing stromal interaction molecules (STIM1 and STIM2) [25].
GtoPdb_general: generated Thu Dec 11 12:34:40 2025; family F977, Orai channels; version 2025.4.
GtoPdb_hierarchy: ( F977 O2964 O2965 O2966 )
2A. Hepatocyte nuclear factor-4 receptors in GtoPdb v.2025.4
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 [80]. HNF4γ has yet to be paired with an endogenous ligand.
GtoPdb_general: generated Thu Dec 11 12:34:36 2025; family F91, 2A. Hepatocyte nuclear factor-4 receptors; version 2025.4.
Voltage-gated sodium channels (NaV) in GtoPdb v.2025.4
Sodium channels are voltage-gated sodium-selective ion channels present in the membrane of most excitable cells. Sodium channels comprise one pore-forming α subunit, which may be associated with either one or two β subunits [191]. 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 [298]. 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 [298]. Auxiliary β1, β2, β3 and β4 subunits consist of a large extracellular N-terminal domain, a single transmembrane segment and a shorter cytoplasmic domain. Pharmacological targeting of voltage-gated sodium channels has long been a cornerstone of clinical treatment for a range of conditions. Classical sodium channel blockers, many of which act by occluding the central pore, are widely used as local anesthetics, antiarrhythmic agents, and anticonvulsants [135]. More recently, suzetrigine, a highly selective Nav1.8 inhibitor, received FDA approval for the treatment of acute post-operative pain [202, 419]. The nomenclature for sodium channels was proposed by Goldin et al., (2000) [155] and approved by the NC-IUPHAR Subcommittee on sodium channels (Catterall et al., 2005, [54]).
GtoPdb_general: generated Thu Dec 11 12:34:36 2025; family F82, Voltage-gated sodium channels (NaV); version 2025.4.
Aquaporins and aquaglyceroporins are membrane channels that allow the permeation of water and certain other small solutes across the cell membrane, or in the case of AQP6, AQP11 and AQP12A, intracellular membranes, such as vesicles and the endoplasmic reticulum membrane [16]. Since the isolation and cloning of the first aquaporin (AQP1) [20], 12 additional mammalian members of the family have been identified, although little is known about the functional properties of one of these (AQP12A; Q8IXF9) and it is thus not tabulated. The other 12 aquaporins can be broadly divided into three families: orthodox aquaporins (AQP0,-1,-2,-4,-5, -6 and -8) permeable mainly to water, but for some additional solutes [4]; aquaglyceroporins (AQP3,-7 -9 and -10), additionally permeable to glycerol and for some isoforms urea [14], and superaquaporins (AQP11 and 12) located within cells [12]. Some aquaporins also conduct ammonia and/or H2O2 giving rise to the terms 'ammoniaporins' ('aquaammoniaporins') and 'peroxiporins', respectively. Aquaporins are impermeable to protons and other inorganic and organic cations, with the possible exception of AQP1, although this is controversial [14]. One or more members of this family of proteins have been found to be expressed in almost all tissues of the body [reviewed in Yang (2017) [27]]. AQPs are involved in numerous processes that include systemic water homeostasis, adipocyte metabolism, brain oedema, cell migration and fluid secretion by epithelia. Loss of function mutations of some human AQPs, or their disruption by autoantibodies further underscore their importance [reviewed by Verkman et al. (2014) [24], Kitchen et al. (2105) [14]]. Functional AQPs exist as homotetramers that are the water conducting units wherein individual AQP subunits (each a protomer) have six TM helices and two half helices that constitute a seventh 'pseudotransmembrane domain' that surrounds a narrow water conducting channel [16]. In addition to the four pores contributed by the protomers, an additional hydrophobic pore exists within the center of the complex [16] that may mediate the transport through AQP1. Although numerous small molecule inhibitors of aquaporins, particularly AQP1, have been reported primarily from Xenopus oocyte swelling assays, the activity of most has subsequently been disputed upon retesting using assays of water transport that are less prone to various artifacts [5] and they are therefore excluded from the tables [see Tradtrantip et al. (2017) [23] for a review].
GtoPdb_general: generated Thu Dec 11 12:34:37 2025; family F119, Aquaporins; version 2025.4.
Calcium activated chloride channel (CaCC) in GtoPdb v.2025.4
Chloride channels activated by intracellular Ca2+ (CaCC) are widely expressed in excitable and non-excitable cells where they perform diverse functions [29]. CaCCs are activated by a rise in intracellular free Ca2+ concentration ([Ca2+]i), typically following activation of Gq protein coupled receptors (GqPCR). This section centres on CaCC channels encoded by the TMEM16A gene (HUGO gene nomenclature: Anoctamin 1). The TMEM16 family consists of 10 paralogs (TMEM16A-K; Anoctamin 1-10). The TMEM16A and TMEM16B genes (ANO1 and ANO2) encode for CaCCs, while the other members function as lipid scramblases or have combined scramblase and non-selective ion channel function [31, 58, 22, 1, 52]. TMEM16A has a broad tissue distribution and a variety of established cellular roles, while the main physiological role for TMEM16B identified thus far is in olfaction [37, 18]. Alternative splicing regulates the voltage- and Ca2+-dependence of TMEM16A and such post-transcriptional process may be tissue-specific and contribute to functional diversity [23]. TMEM16A is a potential drug target for a variety of conditions spanning from respiratory to vascular (see "Comments" section for further detail).
GtoPdb_general: generated Thu Dec 11 12:34:38 2025; family F130, Calcium activated chloride channel (CaCC); version 2025.4.
Epithelial sodium channel (ENaC) in GtoPdb v.2025.4
Overview Epithelial sodium channels (ENaC) are located on the apical membrane of epithelial cells in the kidney tubules, lungs, respiratory tract, male and female reproductive tracts, sweat and salivary glands, placenta, colon, and several other organs [10, 17, 26, 25, 57]. In these epithelia, Na+ ions enter epithelial cells from the extracellular fluid via ENaC and are subsequently pumped out into the interstitial fluid by the Na+/K+-ATPase on the basolateral membrane [49]. Because sodium is a major electrolyte in the extracellular fluid (ECF), the osmotic changes caused by sodium flux are accompanied by parallel water movement [7]. Thus, ENaC plays a central role in regulating ECF volume and blood pressure, primarily through its function in the kidney [51]. The expression of ENaC subunits- and therefore its activity- is controlled by the renin-angiotensin-aldosterone system and other factors involved in electrolyte homeostasis [51, 36]. Genetic studies of systemic pseudohypoaldosteronism type I revealed that ENaC activity depends on three essential subunits encoded by three separate genes encoding homologous proteins [12, 26]. Within the wider protein superfamily that includes ENaC, the first crystal structure determined was that of ASIC, which revealed a trimeric structure with a large extracellular domain anchored in the membrane by a bundle of six transmembrane helices (two per subunit) [3, 30]. The first 3D structure of human ENaC was determined using single-particle cryo-electron microscopy at 3.7Å resolution [45], later improved to 3.0Å [46]. These structures confirmed that ENaC has a quaternary structure similar to ASIC. ENaC assembles as a heterotrimer, with α-, γ-, and β-subunits arranged in clockwise order when viewed from above [13]. In contrast to ASIC1, which can form a functional homotrimer, ENaC is only fully functional as a heterotrimer composed of either αβγ or δβγ [33]. Recently, Houser and Baconguis co-expressed human δ, β, and γ and determined the structures of complexes using single-particle cryoelectron microscopy. The structures showed that β and γ positions are conserved among the different complexes while the α position in the αβγ trimer is occupied by either δ or another β [29]. In the respiratory and female reproductive tracts, large regions of the epithelium consist of multiciliated cells with a microtubule-based cytoskeleton. In these cells, ENaC is distributed along the entire length of the cilia [19]. This localization substantially increases ENaC density on the cell surface and enables precise regulation of periciliary fluid osmolarity throughout its depth [19]. In the vas deferens of the male reproductive tract, the luminal surface is covered with microvilli and stereocilia supported by actin bundles [57]. In these cells, both ENaC and the aquaporin AQP9 are localized to the projections as well as to the basal and smooth muscle layers [57]. In contrast, CFTR- the chloride channel defective in cystic fibrosis- is confined to the apical cell surface but is absent from cilia and microvilli [19, 57]. Collectively, ENaC function regulates epithelial fluid volume, which is essential for mucociliary clearance in the respiratory tract, gamete transport, fertilization, implantation, and cell migration [19, 44, 26]. Genes and Phylogeny The human genome contains four homologous genes (SCNN1A, SCNN1B, SCNN1G, and SCNN1D) encoding the α-, β-, γ-, and δ-ENaC subunits, respectively [11, 40, 55, 62]. These subunits share 23–34% sequence identity and <20% identity with ASIC subunits [26]. Genes encoding all four ENaC subunits are present in bony vertebrates, except in ray-finned fishes, which have lost them entirely. The mouse genome has also lost SCNN1D, the gene for δ-ENaC [21, 26]. The α-, β-, and γ-ENaC genes are present in jawless vertebrates (e.g., lampreys) and cartilaginous fishes (e.g., sharks) [26]. Methylation analysis of the 5′-flanking regions of SCNN1A, SCNN1B, and SCNN1G in human cells revealed an inverse correlation between gene expression and DNA methylation, suggesting epigenetic transcriptional control of ENaC genes [48]. Channel biogenesis, assembly and function ENaC subunit expression is regulated primarily by aldosterone and by numerous other extracellular and intracellular factors [51, 35, 47]. Most studies indicate that expression of the three subunits is not tightly coordinated [9]. However, transport of the subunits to the membrane requires all three intact subunits, and even a single missense mutation can reduce the number of assembled channels on the cell surface [18]. ENaC is constitutively active, meaning Na+ flow does not require an activating factor. Thus, heterologous cells expressing ENaC (e.g., human cRNAs in Xenopus oocytes) must be maintained in amiloride-containing solutions to block channel activity. ENaC activity is then measured by replacing the bath with amiloride-free solution. The channel alternates between two states: 1) open and 2) closed. The probability of ENaC being open is referred to as open probability (Po). ENaC regulation involves two key parameters: (1) membrane channel density and (2) open probability [31, 33]. Open probability is markedly reduced by extracellular Na+ in a process known as sodium self-inhibition [4, 28, 59]. A key regulatory feature is that the α- and γ-subunits contain conserved extracellular serine protease cleavage sites [26]. Proteolytic cleavage by enzymes such as furin and plasmin activates ENaC [52, 34, 1]. Diseases associated with ENaC mutations Mutations in SCNN1A, SCNN1B, or SCNN1G can cause partial or complete loss of ENaC activity [12, 23]. Such loss-of-function mutations are associated with systemic or multi-system autosomal recessive pseudohypoaldosteronism type I (OMIM abbreviation: PHA1B) [22, 12, 26, 64, 19, 54]. No PHA-causing mutations have been identified in SCNN1D. Patients with PHA experience severe salt wasting in all aldosterone target organs expressing ENaC, including kidney, sweat glands, salivary glands, and respiratory tract. In infancy and early childhood, the resulting electrolyte disturbances, dehydration, and acidosis often require recurrent hospitalization. The frequency and severity of salt-wasting episodes generally improve with age [24]. PHA1B also affects female reproductive system function [19, 6]. The ENaC carboxy-terminal region contains a short consensus sequence called the PY motif. Mutations in this motif in SCNN1B and SCNN1G are associated with Liddle syndrome, a disorder marked by early-onset hypertension [60, 5]. The PY motif is recognized by Nedd4-2, a ubiquitin ligase. Mutations that disrupt this recognition reduce ENaC ubiquitylation, leading to channel accumulation at the membrane and increased ENaC activity [53]. ENaC expression in tumors Intracellular sodium concentrations are often elevated in cancer cells compared with normal cells, leading to the hypothesis that ENaC overexpression may contribute to metastasis [39]. However, RNA-seq analysis of ENaC genes and clinical data of cervical cancer patients from The Cancer Genome Atlas (TCGA) revealed a negative correlation with histologic grades of tumor [61]. Similarly, in breast cancer cells, overexpression or siRNA-mediated knockdown of α-ENaC showed that higher α-ENaC levels suppress cell proliferation [63]. In contrast, TCGA data showed that elevated SCNN1A expression correlates with poor prognosis in ovarian cancer [41]. Thus, the role of ENaC in tumorigenesis appears to be tissue-specific. COVID-19 SARS-CoV-2 virions, the cause of COVID-19, are covered with glycosylated spike (S) proteins. These proteins bind to membrane-bound ACE2 as the first step of viral entry. Entry depends on S-protein cleavage (at Arg-667/Ser-668) by a serine protease. Anand et al. identified a sequence motif at this cleavage site homologous to the furin cleavage site in ENaCα [2]. A comprehensive review of COVID-19 pathophysiology suggests a role for ENaC in the early stages of infection in respiratory epithelia [20]. ENaC Inhibitors for Cystic Fibrosis Cystic fibrosis (CF) is the most common life-limiting autosomal recessive disorder among Caucasians. CF is caused by mutations in the gene that codes for CFTR (Cystic Fibrosis Transmembrane Conductance Regulator). CFTR is a chloride and bicarbonate channel located on the apical membrane [14]. CFTR-mediated movement of Cl- and HCO3- ions into the lumen also drives water flow into the lumen by osmosis. CFTR is expressed in many tissues but the most severe effect of mutated CFTR is observed in the respiratory tract in the form of airway surface liquid (ASL) depletion which leads to mucus accumulation, inflammation and bacterial infections that lead to mortality. Normal CFTR activity inhibits ENaC by causing a reduction in surface expression of ENaC as well as its Po [50]. In many epithelia, ENaC and CFTR are not co-localized on the apical membrane indicating that the two channels do not directly interact [19, 56, 57]. In the absence of a functional CFTR, ENaC activity increases (also named as "hyperactivated ENaC"), leading to increased Na+ and water absorption and consequently ASL depletion. These observations have led to the development of inhibitors targeting ENaC in the airways to ameliorate ASL dehydration [58, 43, 38]. Most of the ENaC inhibitors in development are designed for application by inhalation and improved lung retention to avoid damaging the vital activity of ENaC in other tissues [37, 16]. Despite the development of many ENaC inhibitors for CF [15], nearly all drug candidates were discontinued at Preclinical, Phase 1 or Phase 2 stage of clinical trials [38, 16, 43]. However, there is one candidate, EDT001, that is still under Phase 2 clinical trial [16]. The persistence of the scientists and the drug companies and the versatility of their approaches provide hope that an appropriate useful treatment will emerge to help CF patients. Thus, insights into the physiological and pathological roles of ENaC across diverse tissues continue to guide the development of targeted inhibitors, with cystic fibrosis representing a prominent example where modulation of ENaC activity may translate fundamental biology into therapeutic benefit.
GtoPdb_general: generated Thu Dec 11 12:34:38 2025; family F122, Epithelial sodium channel (ENaC); version 2025.4.
Voltage-gated potassium channels (Kv) in GtoPdb v.2025.4
The 6TM family of K channels comprises the voltage-gated KV subfamilies, 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 comprises tetramers of identical subunits (homomeric) or of different subunits (heteromeric). Heteromeric channels can only be formed within subfamilies (e.g. Kv1.1 with Kv1.2; Kv7.2 with Kv7.3). The pharmacology largely reflects the subunit composition of the functional channel.<heading>Kv7 channels</heading>Kv7.1-Kv7.5 (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 [333, 2, 777, 294].
GtoPdb_general: generated Thu Dec 11 12:34:35 2025; family F81, Voltage-gated potassium channels (Kv); version 2025.4.
Acid-sensing (proton-gated) ion channels (ASICs) in GtoPdb v.2025.4
Acid-sensing ion channels (ASICs, nomenclature as agreed by NC-IUPHAR [52, 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 Caenorhabditis elegans, channels in Drosophila melanogaster and the mammalian bile acid-activated ion channel BASIC [94], previously known as BLINaC [75] and INaC [77]. ASIC subunits contain 2 TM domains and a large extracellular part whose shape resembles that of a hand, as shown by high-resolution structures of chicken and human ASIC1a [49, 43, 7, 101, 100, 81]. They assemble as homo- or heterotrimers 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 [48, 93, 52, 74, 23]). Splice variants of ASIC1 [termed ASIC1a (ASIC, ASICα, BNaC2α) [88], ASIC1b (ASICβ, BNaC2β) [19] and ASIC1b2 (ASICβ2) [83]; note that ASIC1a is also permeable to Ca2+], ASIC2 [termed ASIC2a (MDEG1, BNaC1α, BNC1α) [70, 89, 42] and ASIC2b (MDEG2, BNaC1β) [60]] 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) [87] 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 [62]. 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, 47, 35, 58, 24]. 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 [28]. ASICs have also been detected in 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 [59, 29, 46]). A neurotransmitter-like function of protons has been suggested, involving postsynaptically located ASICs of the CNS in functions such as learning and fear perception [36, 54, 104] and of the PNS in mechanoreceptor-neurite transmission [98, 97]. ASIC activation also contributes to cell damage in focal ischemia [95, 73] and autoimmune inflammation (arthritis and multiple sclerosis) [41, 96], as well as neuron activation during seizures and pain [93, 30, 31, 13, 33]. 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 [60, 5, 39, 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) [72, 67]. 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.
GtoPdb_general: generated Thu Dec 11 12:34:37 2025; family F118, Acid-sensing (proton-gated) ion channels (ASICs); version 2025.4.
GtoPdb_hierarchy: ( F118 O684 O685 O686 )
Transient Receptor Potential channels (TRP) in GtoPdb v.2025.4
The TRP superfamily of channels (nomenclature as agreed by NC-IUPHAR [177, 1080]), 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 [734]). 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 [404, 690, 1163, 258]. The established, or potential, involvement of TRP channels in disease [1134] is reviewed in [452, 689], [692] and [468], together with a special edition of Biochemica et Biophysica Acta on the subject [689]. Additional disease related reviews, for pain [637], stroke [1143], sensation and inflammation [994], itch [130], and airway disease [313, 1058], 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 [810]. Most TRP channels are regulated by phosphoinositides 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 [1015, 693, 806]). 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. <heading>TRPA (ankyrin) family</heading> TRPA1 is the sole mammalian member of this group (reviewed by [295]). TRPA1 activation of sensory neurons contribute to nociception [417, 895, 606]. 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 [579, 60, 368, 581]. 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 [428, 515, 1089, 1088]. TRPA1 is not mechanosensitive under physiological conditions, but can be activated by cold temperatures [429, 213]. The electron cryo-EM structure of TRPA1 [745] 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. <heading>TRPC (canonical) family</heading> Members of the TRPC subfamily (reviewed by [286, 783, 18, 4, 94, 450, 744, 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 Gq/11-coupled receptors, or receptor tyrosine kinases (reviewed by [770, 959, 1080]). 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 [451]. TRPC channels have frequently been proposed to act as store-operated channels (SOCs) (or components of multimeric complexes that form SOCs), activated by depletion of intracellular calcium stores (reviewed by [746, 18, 775, 825, 1129, 157, 730, 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 [350, 349]. Activation of TRPC channels by lipids is discussed by [70]. Important progress has been recently made in TRPC pharmacology [810, 623, 440, 102, 856, 192, 293]. TRPC channels regulate a variety of physiological functions and are implicated in many human diseases [298, 71, 890, 1038, 1032, 154, 103, 565, 918, 412]. TRPC1/C4/C5 subgroup TRPC1 alone may not form a functional ion channel [230]. The structures of the apo and antagonist-bound states of TRPC1/TRPC4 heteromeric channels have been resolved by cryo-EM [1070]. 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 [1122, 727, 728, 1123, 543, 1176, 1117]. TRPC3/C6/C7 subgroup All members are activated by diacylglycerol independent of protein kinase C stimulation [350]. <heading>TRPM (melastatin) family</heading> Members of the TRPM subfamily (reviewed by [277, 349, 746, 1159]) 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 [401, 712]. TRPM3 (reviewed by [718]) 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 [947]). 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 [717, 946]. TRPM3 may contribute to the detection of noxious heat [1024]. TRPM2 TRPM2 is activated under conditions of oxidative stress (respiratory burst of phagocytic cells). The direct activators are calcium, adenosine diphosphate ribose (ADPR) [976] and cyclic ADPR (cADPR) [1126]. As for many ion channels, PI(4,5)P2 must also be present [1117]. Numerous splice variants of TRPM2 exist which differ in their activation mechanisms [240]. 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 [390, 1034]. Meanwhile, a quadruple-residue motif (979FGQI982) was identified as the ion selectivity filter and a gate to control ion permeation in hsTRPM2 [1128]. TRPM2 is involved in warmth sensation [853], and contributes to several diseases [76]. TRPM2 interacts with extra synaptic NMDA receptors (NMDAR) and enhances NMDAR activity in ischemic stroke [1172]. Activation of TRPM2 in macrophages promotes atherosclerosis [1173, 1155]. Moreover, silica nanoparticles induce lung inflammation in mice via ROS/PARP/TRPM2 signaling-mediated lysosome impairment and autophagy dysfunction [1035]. 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 [1145, 1147]. TRPM4/5 subgroup TRPM4 and TRPM5 have the distinction within all TRP channels of being impermeable to Ca2+ [1080]. A splice variant of TRPM4 (i.e.TRPM4b) and TRPM5 are molecular candidates for endogenous calcium-activated cation (CAN) channels [330]. TRPM4 is active in the late phase of repolarization of the cardiac ventricular action potential. TRPM4 deletion or knockout enhances beta adrenergic-mediated inotropy [597]. Mutations are associated with conduction defects [407, 597, 884]. TRPM4 has been shown to be an important regulator of Ca2+ entry in to mast cells [999] 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 [541] TRPM5 contributes to the slow afterdepolarization of layer 5 neurons in mouse prefrontal cortex [517]. Both TRPM4 and TRPM5 are required transduction of taste stimuli [247]. TRPM6/7 subgroup TRPM6 and 7 combine channel and enzymatic activities (‘chanzymes’) [173]. 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 [815, 1085]. When either gene is deleted in mice, the result is embryonic lethality [416, 1073]. The C-terminal kinase region of TRPM6 and TRPM7 is cleaved under unknown stimuli, and the kinase phosphorylates nuclear histones [483, 484]. TRPM7 is responsible for oxidant- induced Zn2+ release from intracellular vesicles [3] and contributes to intestinal mineral absorption essential for postnatal survival [626]. The putative metal transporter proteins CNNM1-4 interact with TRPM7 and regulate TRPM7 channel activity [40, 471]. TRPM8 Is a channel activated by cooling and pharmacological agents evoking a ‘cool’ sensation and participates in the thermosensation of cold temperatures [63, 179, 225] reviewed by [1017, 566, 461, 653]. Direct chemical agonists include menthol and icilin[1094]. 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 [516], and have identified cryo-electron microscopy structures of mouse TRPM8 in closed, intermediate, and open states along the ligand- and PIP2-dependent gated pathways [1119]. Moreover, the last 36 amino acids at the carboxyl terminal of TRPM8 are key protein sequences for TRPM8's temperature-sensitive function [195]. 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 [560]. 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 [736]. <heading>TRPML (mucolipin) family</heading> The TRPML family [787, 1140, 780, 1092, 191] 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 [827]. TRPML2 and TRPML3 show increased channel activity in low luminal sodium and/or increased luminal pH, and are activated by similar small molecules [322, 147, 882]. A naturally occurring gain of function mutation in TRPML3 (i.e. A419P) results in the varitint waddler (Va) mouse phenotype (reviewed by [787, 694]). <heading>TRPP (polycystin) family</heading> The TRPP family (reviewed by [217, 215, 303, 1068, 377]) or PKD2 family is comprised of PKD2 (PC2), PKD2L1 (PC2L1), PKD2L2 (PC2L2), which have been renamed TRPP1, TRPP2 and TRPP3, respectively [1080]. It should also be noted that the nomenclature of PC2 was TRPP2 in old literature. However, PC2 has been uniformed to be called TRPP2 [348]. 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. [910]. Although still being sorted out, TRPP family members appear to be 6TM spanning nonselective cation channels. <heading>TRPV (vanilloid) family</heading> Members of the TRPV family (reviewed by [1001]) 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 noxious heat (reviewed by [767, 887, 927]). 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 [849]. The pharmacology of TRPV1 channels is discussed in detail in [332] and [1022]. TRPV2 is probably not a thermosensor in man [740], but has recently been implicated in innate immunity [551]. Functional TRPV2 expression is described in placental trophoblast cells of mouse [205]. 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, 534]. 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 [1064, 206, 655, 272]).TRPV6 is reported to play a key role in calcium transport in the mouse placenta [1063].
GtoPdb_general: generated Thu Dec 11 12:34:34 2025; family F78, Transient Receptor Potential channels (TRP); version 2025.4.
Ionotropic glutamate receptors in GtoPdb v.2025.4
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 [60, 99, 163]. 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) [106, 74, 115, 163, 88]. The X-ray structure of a homomeric ionotropic glutamate receptor (GluA2- see below) has recently been solved at 3.6Å resolution [151] and although providing the most complete structural information current available may not be representative of the subunit arrangement of, for example, the heteromeric NMDA receptors [77]. 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 [60, 72, 34, 83, 44, 122, 27, 71, 163, 120, 121, 171]. 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 [31]. 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 [43, 28]. 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 [50, 106, 77]. 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 [45, 110, 161, 70]). 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; [94, 127, 126]). 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 [127, 71, 126]). Kainate receptors may also exhibit 'metabotropic' functions [94, 139]. As found for AMPA receptors, kainate receptors are modulated by auxiliary subunits (Neto proteins, [126, 95]). An important function difference between AMPA and kainate receptors is that the latter require extracellular Na+ and Cl- for their activation [13, 128]. 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 [147, 69]. 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 [94, 126]. Native AMPA and kainate receptors displaying differential channel conductances, Ca2+ permeabilities and sensitivity to block by intracellular polyamines have been identified [33, 69, 98]. 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 [110]. Splice variants of GluK1-3 also exist which affects their trafficking [94, 126].
GtoPdb_general: generated Thu Dec 11 12:34:34 2025; family F75, Ionotropic glutamate receptors; version 2025.4.
Two-pore domain potassium channels (K2P) in GtoPdb v.2025.4
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 K2P channels (and not two-pore channels). Some of the K2P subunits can form heterodimers across subfamilies (e.g. K2P3.1 with K2P9.1). 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.
GtoPdb_general: generated Thu Dec 11 12:34:35 2025; family F79, Two-pore domain potassium channels (K2P); version 2025.4.
Inwardly rectifying potassium channels (KIR) in GtoPdb v.2025.4
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 (Kir2.x) that are constitutively active, the G protein-activated inward-rectifier K channels (Kir3.x) and the ATP-sensitive K channels (Kir6.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. Kir3.2 with Kir3.3).
GtoPdb_general: generated Thu Dec 11 12:34:33 2025; family F74, Inwardly rectifying potassium channels (KIR); version 2025.4.
The class A orphan GPCRs have been organised into the subfamilies listed below, to better segregate them based on evidence (or lack of evidence) for endogenous ligand or surrogate ligand interactions, and potential for deorphanization.
GtoPdb_general: generated Thu Dec 11 12:34:32 2025; family F16, Class A Orphans; version 2025.4.
Cyclic nucleotide-regulated channels (CNG) in GtoPdb v.2025.4
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 hyperpolarisation-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 Ih, Iq and If. 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 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].
GtoPdb_general: generated Thu Dec 11 12:34:33 2025; family F71, Cyclic nucleotide-regulated channels (CNG); version 2025.4.
Adenosine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adenosine Receptors [114]) are activated by the endogenous ligand adenosine (potentially inosine also at A3 receptors). Crystal and cryo-EM structures for all four adenosine receptors have been solved, occupied by either agonists (sometimes in the presence of an allosteric modulator) or antagonists. Many of these structures were incorporated in a recent review [155]. More recently, structures for the A2B receptor [58, 48] and the A3 receptor [279, 47] were elucidated. The A2A receptor is used as a workhorse in GPCR structure elucidation: almost 100 structures are available in the Protein Data Bank (www.rcsb.org). istradefylline, a selective A2A receptor antagonist, is on the market for the treatment of Parkinson's disease, while caffeine's mechanism of action is largely due to its antagonism of at least three of the four adenosine receptor subtypes. Allosteric modulators, particular PAMs of A1 and A3 receptors, have been explored chemically and structurally [88, 293].
GtoPdb_general: generated Thu Dec 11 12:34:31 2025; family F3, Adenosine receptors; version 2025.4.
GtoPdb_hierarchy: ( F3 O18 O19 O20 O21 I3 )
S33: Prolyl aminopeptidase in GtoPdb v.2025.3
Peptidase family S33 contains mainly exopeptidases that act at the N-terminus of peptides.
GtoPdb_general: generated Tue Oct 7 12:55:40 2025; family F917, S33: Prolyl aminopeptidase; version 2025.3.
GtoPdb_hierarchy: ( F917 O2626 O2875 O1399 )
Receptor guanylyl cyclase (RGC) family in GtoPdb v.2025.3
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.
GtoPdb_general: generated Tue Oct 7 12:55:42 2025; family F1022, Receptor guanylyl cyclase (RGC) family; version 2025.3.
Carnitine palmitoyltransferases in GtoPdb v.2025.3
The CPT1 enzymes convert long chain (greater than ∼C12) acyl-CoA molecules to acylcarnitine derivatives to facilitate their transport from the cytosol into the mitochondrial matrix via the carnitine/acylcarnitine carrier (CACT; SLC25A20). The acylcarnitines are converted back to acyl-CoA by CPT2 to support the fatty acid oxidation (FAO) cycle in the mitochondria. CPT1s are allosterically inhibited by malonyl-CoA.
GtoPdb_general: generated Tue Oct 7 12:55:43 2025; family F1089, Carnitine palmitoyltransferases; version 2025.3.
Endocannabinoid turnover in GtoPdb v.2025.3
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 [32]. FABP5 (Q01469) has been suggested to act as a canonical intracellular endocannabinoid transporter in vivo [19]. 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, [79]). A transacylation enzyme which forms N-acylphosphatidylethanolamines has been identified as a cytosolic enzyme, PLA2G4E (Q3MJ16) [70]. In vitro experiments indicate that the endocannabinoids are also substrates for oxidative metabolism via cyclooxygenase, lipoxygenase and cytochrome P450 enzyme activities [6, 26, 81].
GtoPdb_general: generated Tue Oct 7 12:55:41 2025; family F943, Endocannabinoid turnover; version 2025.3.
Coronavirus (CoV) proteins in GtoPdb v.2025.3
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).
GtoPdb_general: generated Tue Oct 7 12:55:43 2025; family F1034, Coronavirus (CoV) proteins; version 2025.3.
SLC54 Mitochondrial pyruvate carriers in GtoPdb v.2025.3
The mitochondrial pyruvate carrier (MPC) is composed of SLC54 family members (MPC1 or MPC1L and MPC2) [1, 5, 10], which form functional hetero-dimers [9, 8]. The MPC is expressed in the inner mitochondrial membrane and is responsible for the import of pyruvate into mitochondria [1, 5]. Pyruvate is oxidized to acetyl-CoA by pyruvate dehydrogenase which is localized in the mitochondrial matrix. 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].
GtoPdb_general: generated Tue Oct 7 12:55:41 2025; family F1006, SLC54 Mitochondrial pyruvate carriers; version 2025.3.
E3 ubiquitin ligase components in GtoPdb v.2025.3
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) [50]. 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 [5], through the development of proteolysis targeting chimeras (PROTACs) and molecular glues.
GtoPdb_general: generated Tue Oct 7 12:55:42 2025; family F1023, E3 ubiquitin ligase components; version 2025.3.
Blood coagulation components in GtoPdb v.2025.3
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.
GtoPdb_general: generated Tue Oct 7 12:55:39 2025; family F853, Blood coagulation components; version 2025.3.
Regulators of G protein Signaling (RGS) proteins in GtoPdb v.2025.3
Regulator of G protein Signaling, or RGS, proteins serve an important regulatory role in signaling mediated by G protein-coupled receptors (GPCRs). They all share a common RGS domain that directly interacts with active, GTP-bound Gα subunits of heterotrimeric G proteins. RGS proteins stabilize the transition state for GTP hydrolysis on Gα and thus induce a conformational change in the Gα subunit that accelerates GTP hydrolysis, thereby effectively turning off signaling cascades mediated by GPCRs. This GTPase accelerating protein (GAP) activity is the canonical mechanism of action for RGS proteins, although many also possess additional functions and domains. RGS proteins are divided into four families, R4, R7, R12 and RZ based on sequence homology, domain structure as well as specificity towards Gα subunits. For reviews on RGS proteins and their potential as therapeutic targets, see e.g. [226, 530, 579, 584, 585, 744, 755, 445, 11].
GtoPdb_general: generated Tue Oct 7 12:55:39 2025; family F891, Regulators of G protein Signaling (RGS) proteins; version 2025.3.
Peptidyl-prolyl cis/trans isomerases in GtoPdb v.2025.3
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 [65], and family members have been targetted for immunosuppressant effects.
GtoPdb_general: generated Tue Oct 7 12:55:38 2025; family F845, Peptidyl-prolyl cis/trans isomerases; version 2025.3.
The RAS proteins (HRAS, NRAS and KRAS) are small membrane-localised G protein-like molecules of 21 kd. They act as an on/off switch linking receptor and non-receptor tyrosine kinase activation to downstream cytoplasmic or nuclear events. Binding of GTP activates the switch, and hydrolysis of the GTP to GDP inactivates the switch. The RAS proto-oncogenes are the most frequently mutated class of proteins in human cancers. Common mutations compromise the GTP-hydrolysing ability of the proteins causing constitutive activation [38], which leads to increased cell proliferation and decreased apoptosis [49]. Because of their importance in oncogenic transformation these proteins have become the targets of intense drug discovery effort [2].
GtoPdb_general: generated Tue Oct 7 12:55:40 2025; family F897, RAS subfamily; version 2025.3.
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.
GtoPdb_general: generated Tue Oct 7 12:55:38 2025; family F799, Hydrolases & Lipases; version 2025.3.
3.6.5.2 Small monomeric GTPases in GtoPdb v.2025.3
GtoPdb_general: generated Tue Oct 7 12:55:40 2025; family F896, 3.6.5.2 Small monomeric GTPases; version 2025.3.