Neuropeptide Y

Overview: Neuropeptide Y (NPY) receptors (nomenclature agreed by NC-IUPHAR on Neuropeptide Y Receptors, see Michel et al., 1998) are activated by the endogenous peptides NPY, NPY-(3-36), peptide YY (PYY), 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, Loetscher et al., 1994). 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 (Gregor et al., 1996). Many of the agonists exhibit differing degrees of selectivity dependent on the species examined. For example, the relative potency of PP is greater at the rat Y₄ receptor than at the human receptor (Eriksson et al., 1998). 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.

Nomenclature	Y1	Y2	Y4	Y5	y6
Other names	–	–	PP1	–	Y5, PP2, Y2B
Ensembl ID	ENSG00000164128	ENSG00000185149	ENSG00000169556	ENSG00000164129	ENSG00000159279
Principal transduction	Gi/o	Gi/o	Gi/o	Gi/o	Gi/o
Rank order of potency	NPY ≥ PYY >> PP	NPY ≥ PYY >> PP	PP > NPY = PYY	NPY ≥ PYY ≥ PP	NPY = PYY > PP
Selective agonists	[Leu31,Pro34]NPY, [Pro34]NPY, [Leu31,Pro34]PYY, [Pro34]PYY	NPY-(3-36), PYY-(3-36)	PP	[Ala31,Aib32]NPY (Cabrele et al., 2000)	–
Selective antagonists	BIBO3304 (9.5, Wieland et al., 1998), BIBP3226 (8.2, Gerald et al., 1996)	BIIE0246 (8.5, Doods et al., 1999), JNJ5207787 (Bonaventure et al., 2004)	–	L152804 (7.6, Kanatani et al., 2000)	–
Probes	[125I]-[Leu31,Pro34] NPY, [3H]-BIBP3226 (2.1 nM)	[125I]-PYY-(3-36)	[125I]-PP	[125I]-[cPP(1-7),NPY(19-23), Ala31,Aib32,Gln34]hPP (Dumont et al., 2004)	–

The Y₁ agonists indicated are selective relative to Y₂ receptors. BIBP3226 is selective relative to Y₂, Y₄ and Y₅ receptors (Gerald et al., 1996). NPY-(13-36) is Y₂-selective relative to Y₁ and Y₅ receptors. PYY-(3-36) is Y₂ selective relative to Y₁-receptors.

Glossary

Abbreviations:

BIBO3304

(r)-N-([4-{aminocarbonylaminomethyl}-phenyl]methyl)-N²-(diphenylacetyl)-argininamide trifluoroacetate

BIBP3226

r-N²-(diphenylacetyl)-N-(4-hydroxyphenyl)methyl-argininamide

BIIE0246

(s)-N²-([1-{2-(4-[(r,s)-5,11-dihydro-6(6H)-oxodibenz[b,e]azepin-11-yl]-1-piperazinyl)-2-oxoethyl}cyclopentyl]acetyl)-N-(2-[1,2-dihydro-3,5(4H)-dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl]ethyl)-argininamide

JNJ5207787

N-(1-acetyl-2,3-dihydro-1H-indol-6-yl)-3-(3-cyano-phenyl)-N-[1-(2-cyclopentylethyl)piperidin-4-yl]acrylamide

L152804

2-(3,3-dimethyl-1-oxo-4H-1H-xanthen-9-yl)-5,5-dimethyl-cyclohexane-1,3-dione

Further Reading

Larhammar D, Salaneck E (2004). Molecular evolution of NPY receptor subtypes. Neuropeptides38: 141–151.

Lunniss GE, Barnes AA, Barton N, Biagetti M, Bianchi F, Blowers SM et al. (2009). The identification and optimisation of novel and selective diamide neuropeptide Y Y2 receptor antagonists. Bioorg Med Chem Lett19: 4022–4025.

Michel MC (2004). Neuropeptide Y and related peptides. Handb Exp Pharmacol162: 1–555.

Michel MC, Beck-Sickinger A, Cox H, Doods HN, Herzog H, Larhammar D et al. (1998). International Union of Pharmacology XVI. Recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors. Pharmacol Rev50: 143–150.

Nygaard R, Nielbo S, Schwartz TW, Poulsen FM (2006). The PP-fold solution structure of human polypeptide YY and human PYY3-36 as determined by NMR. Biochemistry45: 8350–8357.

Parker E, Van Heek M, Stamford A (2002). Neuropeptide Y receptors as targets for anti-obesity drug development: perspective and current status. Eur J Pharmacol440: 173–187.

Pedrazzini T (2004). Importance of NPY Y₁ receptor-mediated pathways: assessment using NPY Y1 receptor knockouts. Neuropeptides38: 267–275.

Tough IR, Holliday ND, Cox HM (2006). Y₄ receptors mediate the inhibitory responses of pancreatic polypeptide in human and mouse colon mucosa. J Pharmacol Exp Ther319: 20–30.