Receptor subtypes Y₁ and Y₅ mediate neuropeptide Y induced feeding in the guinea‐pig

Abstract

1 Neuropeptide Y (NPY) is one of the most potent stimulants of food intake. It has been debated which receptor subtype mediates this response. Initially Y 1 was proposed, but later Y 5 was announced as a`feeding' receptor in rats and mice. Very little is known regarding other mammals. The present study attempts to characterize the role of NPY in feeding behaviour in the distantly related guinea-pig. When infused intracerebroventricularly, NPY dose-dependently increased food intake. 2 PYY, (Leu 31 ,Pro 34 )NPY and NPY(2 ± 36) stimulated feeding, whereas NPY(13 ± 36) had no e ect. These data suggest that either Y 1 or Y 5 receptors or both may mediate NPY induced food intake in guinea-pigs. 3 The Y 1 receptor antagonists, BIBO 3304 and H 409/22 displayed nanomolar a nity for the Y 1 receptor (K i values 1.1+0.2 nM and 5.6+0.9 nM, respectively), but low a nity for the Y 2 or Y 5 receptors. When guinea-pigs were pretreated with BIBO 3304 and H 409/22, the response to NPY was inhibited. 4 The Y 5 antagonist, CGP 71683A had high a nity for the Y 5 receptor (K i 1.3+0.05 nM) without having any signi®cant activities at the Y 1 and Y 2 receptors. When CGP 71683A was infused into brain ventricles, the feeding response to NPY was attenuated. 5 The present study shows that NPY stimulates feeding in guinea-pigs through Y 1 and Y 5 receptors. As the guinea-pig is very distantly related to the rat and mouse, this suggests that both Y 1 and Y 5 receptors may mediate NPY-induced hyperphagia also in other orders of mammals.

A G Protein–Coupled Receptor Dimer Imaging Assay Reveals Selectively Modified Pharmacology of Neuropeptide Y Y1/Y5 Receptor Heterodimers

“…125 I]PYY binding studies indicated that this construct displayed high affinities for the agonist PYY and the nonpeptide Y1 antagonist BIBO3304 (Wieland et al, 1998;Lecklin et al, 2002) (Table 1), equivalent to those we have previously reported for native and fluorescent protein-modified Y1 receptors (Kilpatrick et al, 2010(Kilpatrick et al, , 2012, and an estimated [ (Table 1) (Kilpatrick et al, 2010). Automated confocal imaging studies (Fig.…”

“…NPY is a widely expressed central nervous system modulator, noted for its role in appetite regulation when released from hypothalamic arcuate neurons (Michel et al, 1998;Brothers and Wahlestedt, 2010). Orexigenic effects of NPY are mediated through a combination of Y1 and Y5 receptor subtypes coexpressed in paraventricular target cells (Gerald et al, 1996;Cabrele et al, 2000;Lecklin et al, 2002;Brothers and Wahlestedt, 2010). Y1 antagonists [e.g., (R)-N 2 -(diphenylacetyl)-N-[(4-(aminocarbonylaminomethyl)phenyl) methyl]-argininamide (BIBO3304); Wieland et al, 1998] and Y5 antagonists [e.g., N-[[trans-4-[[(4-amino-2-quinazolinyl) amino]methyl]cyclohexyl]methyl]-1-naphthalene sulfonamide hydrochloride (CGP71683); Criscione et al, 1998] were explored for their abilities to inhibit appetite.…”

Therapy for Obesity Based on Gastrointestinal Hormones

“…However, the anorectic effect of PYY seems to be mediated by by PYY (3-36), but not by PYY ). This appears to be due to the specific affinity of the dominating peptide PYY(3-36) for the Y2 receptor, and due to the fact that the Y1 and Y5 receptors are associated with increased feeding behavior [75].…”

Receptor Subtype-specific Docking of Asp6.59 with C-terminal Arginine Residues in Y Receptor Ligands

“…All members are C-terminally amidated polypeptides consisting of 36 amino acids (1) and are involved in multiple physiological processes, including memory retention (2, 3), feeding behavior (4,5), control of blood pressure (6,7), and seizure (8).…”

“…Y 1 R and Y 4 R require the complete N terminus of the ligand (15,19,20). Y 5 R accepts peptides with the deletion of the first amino acid (21), and Y 2 R even binds significantly shorter peptides (NPY ) or centrally truncated analogs ([Ahx [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] ]NPY) with only minor effects on affinity (19,22). However, the C-terminal pentapeptide of all natural ligands was identified as an essential region for binding to all YRs (23,24), and these residues of the ligand C terminus seem to represent a core contact domain.…”