Neuropeptide Y (NPY) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Neuropeptide Y Receptors [17]) are activated by the endogenous peptides neuropeptide Y (NPY, P01303), neuropeptide Y-(3-36), peptide YY (PYY, P10082), PYY-(3-36) and pancreatic polypeptide (PPY, P01298) (PP). The receptor originally identified as the Y3 receptor has been identified as the CXCR4 chemokine recepter (originally named LESTR, [15]). 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 [12]. Three-dimensional structures have been determined for subtype active receptors Y₁, Y₂ and Y₄ [14,22] and inactive antagonist bound Y₁ and Y₂ receptors [21,27]. 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 Y₄ receptor than at the human receptor [8]. 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).

The Y₁ agonists indicated are selective relative to Y₂ receptors. BIBP3226 is selective relative to Y₂, Y₄ and Y₅ receptors [10]. NPY-(13-36) is Y₂ selective relative to Y₁ and Y₅ receptors. PYY-(3-36) is Y₂ selective relative to Y₁ receptors. Note that Pro34-containing NPY and PYY can also bind Y₄ and Y₅, thus they are selective only relative to Y₂. The y₆ receptor is a pseudogene in humans, but is functional in mouse, rabbit and some other mammals.

* Key recommended reading is highlighted with an asterisk

* Bowers ME, Choi DC, Ressler KJ. (2012) Neuropeptide regulation of fear and anxiety: Implications of cholecystokinin, endogenous opioids, and neuropeptide Y. Physiol Behav, 107 (5): 699-710. [PMID:22429904]

Decressac M, Barker RA. (2012) Neuropeptide Y and its role in CNS disease and repair. Exp Neurol, 238 (2): 265-72. [PMID:23022456]

Holzer P, Reichmann F, Farzi A. (2012) Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut-brain axis. Neuropeptides, 46 (6): 261-74. [PMID:22979996]

* Michel MC, Beck-Sickinger A, Cox H, Doods HN, Herzog H, Larhammar D, Quirion R, Schwartz T, Westfall T. (1998) XVI. International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors. Pharmacol Rev, 50 (1): 143-50. [PMID:9549761]

Morales-Medina JC, Dumont Y, Quirion R. (2010) A possible role of neuropeptide Y in depression and stress. Brain Res, 1314: 194-205. [PMID:19782662]

* Pedragosa-Badia X, Stichel J, Beck-Sickinger AG. (2013) Neuropeptide Y receptors: how to get subtype selectivity. Front Endocrinol (Lausanne), 4: 5. [PMID:23382728]

Zengin A, Zhang L, Herzog H, Baldock PA, Sainsbury A. (2010) Neuropeptide Y and sex hormone interactions in humoral and neuronal regulation of bone and fat. Trends Endocrinol Metab, 21 (7): 411-8. [PMID:20202858]

* Zhang L, Bijker MS, Herzog H. (2011) The neuropeptide Y system: pathophysiological and therapeutic implications in obesity and cancer. Pharmacol Ther, 131 (1): 91-113. [PMID:21439311]

1. Bard JA, Walker MW, Branchek TA, Weinshank RL. (1995) Cloning and functional expression of a human Y4 subtype receptor for pancreatic polypeptide, neuropeptide Y, and peptide YY. J Biol Chem, 270 (45): 26762-5. [PMID:7592911]

2. Bonaventure P, Nepomuceno D, Mazur C, Lord B, Rudolph DA, Jablonowski JA, Carruthers NI, Lovenberg TW. (2004) Characterization of N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-3-(3-cyano-phenyl)-N-[1-(2-cyclopentyl-ethyl)-piperidin-4yl]acrylamide (JNJ-5207787), a small molecule antagonist of the neuropeptide Y Y2 receptor. J Pharmacol Exp Ther, 308 (3): 1130-7. [PMID:14617685]

3. Cabrele C, Wieland HA, Koglin N, Stidsen C, Beck-Sickinger AG. (2002) Ala31-Aib32: identification of the key motif for high affinity and selectivity of neuropeptide Y at the Y5-receptor. Biochemistry, 41 (25): 8043-9. [PMID:12069595]

4. Cox HM, Tough IR. (1995) Functional characterization of receptors with affinity for PYY, NPY, [Leu31,Pro34]NPY and PP in a human colonic epithelial cell line. Br J Pharmacol, 116 (6): 2673-8. [PMID:8590988]

5. Doods H, Gaida W, Wieland HA, Dollinger H, Schnorrenberg G, Esser F, Engel W, Eberlein W, Rudolf K. (1999) BIIE0246: a selective and high affinity neuropeptide Y Y(2) receptor antagonist. Eur J Pharmacol, 384 (2-3): R3-5. [PMID:10611450]

6. Doods HN, Wienen W, Entzeroth M, Rudolf K, Eberlein W, Engel W, Wieland HA. (1995) Pharmacological characterization of the selective nonpeptide neuropeptide Y Y1 receptor antagonist BIBP 3226. J Pharmacol Exp Ther, 275 (1): 136-42. [PMID:7562541]

7. Dumont Y, Thakur M, Beck-Sickinger A, Fournier A, Quirion R. (2004) Characterization of a new neuropeptide Y Y5 agonist radioligand: [125I][cPP(1-7), NPY(19-23), Ala31, Aib32, Gln34]hPP. Neuropeptides, 38 (4): 163-74. [PMID:15337369]

8. Eriksson H, Berglund MM, Holmberg SK, Kahl U, Gehlert DR, Larhammar D. (1998) The cloned guinea pig pancreatic polypeptide receptor Y4 resembles more the human Y4 than does the rat Y4. Regul Pept, 75-76: 29-37. [PMID:9802391]

9. Gehlert DR, Beavers LS, Johnson D, Gackenheimer SL, Schober DA, Gadski RA. (1996) Expression cloning of a human brain neuropeptide Y Y2 receptor. Mol Pharmacol, 49 (2): 224-8. [PMID:8632753]

10. Gerald C, Walker MW, Criscione L, Gustafson EL, Batzl-Hartmann C, Smith KE, Vaysse P, Durkin MM, Laz TM, Linemeyer DL et al.. (1996) A receptor subtype involved in neuropeptide-Y-induced food intake. Nature, 382 (6587): 168-71. [PMID:8700207]

11. Gerald C, Walker MW, Vaysse PJ, He C, Branchek TA, Weinshank RL. (1995) Expression cloning and pharmacological characterization of a human hippocampal neuropeptide Y/peptide YY Y2 receptor subtype. J Biol Chem, 270 (45): 26758-61. [PMID:7592910]

12. Gregor P, Millham ML, Feng Y, DeCarr LB, McCaleb ML, Cornfield LJ. (1996) Cloning and characterization of a novel receptor to pancreatic polypeptide, a member of the neuropeptide Y receptor family. FEBS Lett, 381: 58-62. [PMID:8641440]

13. Kanatani A, Ishihara A, Iwaasa H, Nakamura K, Okamoto O, Hidaka M, Ito J, Fukuroda T, MacNeil DJ, Van der Ploeg LH et al.. (2000) L-152,804: orally active and selective neuropeptide Y Y5 receptor antagonist. Biochem Biophys Res Commun, 272 (1): 169-73. [PMID:10872822]

14. Kang H, Park C, Choi YK, Bae J, Kwon S, Kim J, Choi C, Seok C, Im W, Choi HJ. (2023) Structural basis for Y2 receptor-mediated neuropeptide Y and peptide YY signaling. Structure, 31 (1): 44-57.e6. [PMID:36525977]

15. Loetscher M, Geiser T, O'Reilly T, Zwahlen R, Baggiolini M, Moser B. (1994) Cloning of a human seven-transmembrane domain receptor, LESTR, that is highly expressed in leukocytes. J Biol Chem, 269 (1): 232-7. [PMID:8276799]

16. Lundell I, Blomqvist AG, Berglund MM, Schober DA, Johnson D, Statnick MA, Gadski RA, Gehlert DR, Larhammar D. (1995) Cloning of a human receptor of the NPY receptor family with high affinity for pancreatic polypeptide and peptide YY. J Biol Chem, 270 (49): 29123-8. [PMID:7493937]

17. Michel MC, Beck-Sickinger A, Cox H, Doods HN, Herzog H, Larhammar D, Quirion R, Schwartz T, Westfall T. (1998) XVI. International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors. Pharmacol Rev, 50 (1): 143-50. [PMID:9549761]

18. Petitto JM, Huang Z, McCarthy DB. (1994) Molecular cloning of NPY-Y1 receptor cDNA from rat splenic lymphocytes: evidence of low levels of mRNA expression and [125I]NPY binding sites. J Neuroimmunol, 54 (1-2): 81-6. [PMID:7929806]

19. Schüß C, Vu O, Schubert M, Du Y, Mishra NM, Tough IR, Stichel J, Weaver CD, Emmitte KA, Cox HM et al.. (2021) Highly Selective Y₄ Receptor Antagonist Binds in an Allosteric Binding Pocket. J Med Chem, 64 (5): 2801-2814. [PMID:33595306]

20. Schubert M, Stichel J, Du Y, Tough IR, Sliwoski G, Meiler J, Cox HM, Weaver CD, Beck-Sickinger AG. (2017) Identification and Characterization of the First Selective Y₄ Receptor Positive Allosteric Modulator. J Med Chem, 60 (17): 7605-7612. [PMID:28795803]

21. Tang T, Hartig C, Chen Q, Zhao W, Kaiser A, Zhang X, Zhang H, Qu H, Yi C, Ma L et al.. (2021) Structural basis for ligand recognition of the neuropeptide Y Y₂ receptor. Nat Commun, 12 (1): 737. [PMID:33531491]

22. Tang T, Tan Q, Han S, Diemar A, Löbner K, Wang H, Schüß C, Behr V, Mörl K, Wang M et al.. (2022) Receptor-specific recognition of NPY peptides revealed by structures of NPY receptors. Sci Adv, 8 (18): eabm1232. [PMID:35507650]

23. Tough IR, Holliday ND, Cox HM. (2006) Y(4) receptors mediate the inhibitory responses of pancreatic polypeptide in human and mouse colon mucosa. J Pharmacol Exp Ther, 319 (1): 20-30. [PMID:16807358]

24. Wieland HA, Engel W, Eberlein W, Rudolf K, Doods HN. (1998) Subtype selectivity of the novel nonpeptide neuropeptide Y Y1 receptor antagonist BIBO 3304 and its effect on feeding in rodents. Br J Pharmacol, 125: 549-555. [PMID:9806339]

25. Wieland HA, Willim KD, Entzeroth M, Wienen W, Rudolf K, Eberlein W, Engel W, Doods HN. (1995) Subtype selectivity and antagonistic profile of the nonpeptide Y1 receptor antagonist BIBP 3226. J Pharmacol Exp Ther, 275 (1): 143-9. [PMID:7562543]

26. Yan H, Yang J, Marasco J, Yamaguchi K, Brenner S, Collins F, Karbon W. (1996) Cloning and functional expression of cDNAs encoding human and rat pancreatic polypeptide receptors. Proc Natl Acad Sci USA, 93 (10): 4661-5. [PMID:8643460]

27. Yang Z, Han S, Keller M, Kaiser A, Bender BJ, Bosse M, Burkert K, Kögler LM, Wifling D, Bernhardt G et al.. (2018) Structural basis of ligand binding modes at the neuropeptide Y Y₁ receptor. Nature, 556 (7702): 520-524. [PMID:29670288]

Subcommittee members: Dan Larhammar (Chairperson) (Past contributor) Department of Neuroscience Unit of Pharmacology Uppsala University Box 593 SE-75124 Uppsala Sweden Annette G. Beck-Sickinger Institut für Biochemie Universität Leipzig Talstrasse 33 Leipzig 04103 Germany William F. Colmers Professor of Pharmacology and AHFMR Medical Scientist Department of Pharmacology University of Alberta 9-36 MSB Edmonton AB T6G 2H7 Canada Helen M. Cox Centre for Neuroscience Research Kings College London GKT School of Biomedical Sciences Guy's Campus St. Thomas Street London SE1 9RT UK Herbert Herzog Garvan Institute of Medical Research St. Vincent Hospital 384 Victoria Street, Darlinghurst Sydney NSW 2010 Australia Remi Quirion Department of Psychiatry Douglas Hospital Research Centre McGill University 6875 LaSalle Boulevard Verdun Québec H4H 1R3 Canada Thue Schwartz Laboratory of Molecular Pharmacology Department of Pharmacology The Panum Institute 18.6 Blegdamsvej 3 Copenhagen 2200 Denmark Thomas Westfall Department of Pharmacology St. Louis University 1402 South Grand Boulevard St. Louis MO 63104-1079 USA