Cloning and Functional Expression of a Human Y4 Subtype Receptor for Pancreatic Polypeptide, Neuropeptide Y, and Peptide YY

Bard, Jonathan; Walker, Mary W.; Branchek, Theresa A.; Weinshank, Richard L.

doi:10.1074/jbc.270.45.26762

Cited by 350 publications

(203 citation statements)

References 32 publications

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“…6 Both peptides are thought to bind to the hypothalamic Y-family receptors. PP binds primarily to the Y4 receptor 7 and PYY 3À36 binds predominantly to the Y2 receptor. 8 In addition to their central actions, PP and PYY may also inhibit food intake through a reduction in gut motility.…”

Section: Introductionmentioning

confidence: 99%

No evidence of an additive inhibitory feeding effect following PP and PYY3−36 administration

et al. 2008

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Pancreatic polypeptide (PP) and peptide YY (PYY) are released by the gut in response to nutrients and inhibit food intake in rodents and humans. We hypothesized that PP and PYY 3À36 would inhibit feeding additively. Fasted male C57BL/6 mice were injected intraperitoneally with saline, PP, PYY 3À36 or PP þ PYY 3À36 (n ¼ 7-10). Food intake at 1 h was significantly inhibited by 6 nmol kg À1 PP and by 6 nmol kg À1 PYY 3-36 (Po0.05) but not significantly following 3 nmol kg À1 PP þ 3 nmol kg À1 PYY 3À36 . In a higher dose study 30 nmol kg À1 PP, 30 nmol kg À1 PYY 3À36 and 30 nmol kg À1 PP þ 30 nmol kg À1 PYY 3À36 all inhibited 1 h food intake compared with saline (Po0.05) but there was no significant difference in the food intake of the combined group compared with either hormone individually. Subsequently, 16 fasted lean healthy human volunteers (6 men and 10 women) received, in random order, 90 min intravenous infusions of saline, 4 pmol kg À1 min À1 PP, 0.4 pmol kg À1 min À1 PYY 3À36 and 4 pmol kg À1 min À1 PP þ 0.4 pmol kg À1 min À1 PYY 3À36 . A pasta lunch was served 60 min following infusion. There was no evidence of a greater decrease in food intake with the combined PP þ PYY 3À36 treatment (buffet meal energy intake (KJ): saline 2633 ± 204, PP þ PYY 2693 ± 254, PP 2367 ± 199, PYY 2511 ± 196). These results suggest that PP and PYY 3À36 do not inhibit feeding additively in rodents or humans.

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Section: Introductionmentioning

confidence: 99%

No evidence of an additive inhibitory feeding effect following PP and PYY3−36 administration

et al. 2008

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“…NPY is one of the most abundant neurohormones in the mammalian peripheral and central nervous systems. Receptor competition binding studies using analogs or segments of NPY, PYY and PP revealed that at least four receptor subtypes (YI, Y2, Y3, Y4) exist [4,5]. The Y1, Y2, and Y4 receptors have been cloned recently and it could be shown that they all belong to the G-protein coupled receptor family.…”

Section: Introductionmentioning

confidence: 99%

“…The Y1, Y2, and Y4 receptors have been cloned recently and it could be shown that they all belong to the G-protein coupled receptor family. Whereas NPY shows high affinity to Y1 and Y2 receptors, PP is supposed to be the endogenous ligand of the Y4 receptor [5].…”

Section: Introductionmentioning

confidence: 99%

Modified, cyclic dodecapeptide analog of neuropeptide Y is the smallest full agonist at the human Y₂ receptor

et al. 1996

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In order to stabilize the C-terminal dodecapeptide of neuropeptide Y (NPY) we replaced Leu 2s and Thr 32 by Lys and Glu, respectively, and subsequently linked these residues by lactamization. This peptide analog of NPY shows a more than 100-fold increase in affinity compared to the C-terminal linear dodecapeptide in receptor binding studies performed at human neuroblastoma cells SMS-KAN, which exclusively express the Y2 receptor subtype.2+ Signal transduction was investigated" by measuring Ca current inhibition in human SH-SY5Y cells and cyclic [Lys2S-Glu3Z] NPY Ac-25-36 and NPY were shown to be equipotent in this assay. Thus, this molecule is the smallest Y2 receptor selective full agonist of NPY. Using 2D-NMR experiments and molecular modelling techniques, the structures of the linear and cyclic peptides have been investigated and significant differences have been found, which may explain the improvement in biological activity. Thus, a model of the bioactive conformation of NPY at the human Yz receptor is suggested.

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“…[25,26]. A putative Y 3 -receptor has been described only pharmacologically and no specific agonists or antagonists are known [27].…”

mentioning

confidence: 99%

“…Its wide range of action is exerted via several receptor subtypes, named Y 1 -[17±19], Y 2 -[20±22], Y 5 - [23] and y 6 - [24] receptor subtypes, whereas the related peptide PP binds to the Y 4 /PP 1 -receptor [25,26]. A putative Y 3 -receptor has been described only pharmacologically and no specific agonists or antagonists are known [27].…”

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confidence: 99%

Novel analogues of neuropeptide Y with a preference for the Y₁‐receptor

Söll

Dinger

Lundell

et al. 2001

European Journal of Biochemistry

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In contrast, cyclo S±S [Cys20,Cys24]pNPY was found to be a highly selective ligand at the Y 2 -receptor, binding only threefold less efficiently than NPY. Analogues containing variations of positions 31 and 32 showed highly reduced affinity to the Y 1 -receptor, while binding to the Y 5 -receptor was affected less. Inhibition of cAMP-accumulation of selected peptides with replacements within position 20±23 of NPY showed preserved agonistic properties. The NPY analogues tested give insights into ligand±receptor interaction of NPY at the Y 1 -, Y 2 -and Y 5 -receptor and contribute to our understanding of subtype selectivity. Furthermore, the Y 1 -receptor-preferring peptides are novel tools that will provide insight into the physiological role of the Y 1 -receptor.Keywords: food intake; neuropeptides; NPY; selective ligands; structure±affinity relationship.Obesity, food intake and energy homeostasis are key areas of growing importance because obesity is beginning to replace malnutrition and infectious diseases as the most significant contributor to ill health in the developed world [1]. Neuropeptide Y (NPY) is one of the most important effector molecules of leptin: it is a key molecule in the regulation of food intake, it acts via several different receptor subtypes and elicits several physiological effects. Profound effects on stimulation of food intake, secretion of luteinizing and growth hormone, and insulin release suggest an important role for NPY in the pathophysiology of obesity and diabetes [2±5]. A wide range of other effects of NPY have been reported, such as potent vasoconstriction [6], facilitation of learning and memory [7], modulation of locomotor behaviours [8], induction of hypothermia [9,10], inhibition of sexual behaviour [11], shifts in circadian rhythms [12], modulation of cardiorespiratory parameters[13], anxiolytic potency [14] and inhibition of alcohol consumption and resistance [15].NPY is a 36-amino acid peptide amide belonging to the family of pancreatic polypeptides that includes also pancreatic polypeptide (PP) and peptide YY; it was first isolated from pig brain in 1982 [16].NPY is widely distributed within the central nervous system and in the periphery. [25,26]. A putative Y 3 -receptor has been described only pharmacologically and no specific agonists or antagonists are known [27]. All receptors belong to the G-protein coupled receptor superfamily [28]. The correlation of a certain receptor subtype to a distinct physiological effect is not yet fully understood. Recent studies even suggest that different receptor subtypes redundantly mediate identical actions in a given system, as has been shown for the Y 1 -and Y 5 -receptor in the regulation of food intake [3]. Findings that deficiencies in either the Y 1 -or the Y 5 -receptors do not significantly impair the normal feeding response to fasting or NPY stimulation, strongly indicate that both Y receptors are involved in appetite regulation by NPY [29,30]. Selective receptor agonists or antagonists are useful tools with which to stu...

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Cloning and Functional Expression of a Human Y4 Subtype Receptor for Pancreatic Polypeptide, Neuropeptide Y, and Peptide YY

Cited by 350 publications

References 32 publications

No evidence of an additive inhibitory feeding effect following PP and PYY3−36 administration

No evidence of an additive inhibitory feeding effect following PP and PYY3−36 administration

Modified, cyclic dodecapeptide analog of neuropeptide Y is the smallest full agonist at the human Y₂ receptor

Novel analogues of neuropeptide Y with a preference for the Y₁‐receptor

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Cloning and Functional Expression of a Human Y4 Subtype Receptor for Pancreatic Polypeptide, Neuropeptide Y, and Peptide YY

Cited by 350 publications

References 32 publications

No evidence of an additive inhibitory feeding effect following PP and PYY3−36 administration

No evidence of an additive inhibitory feeding effect following PP and PYY3−36 administration

Modified, cyclic dodecapeptide analog of neuropeptide Y is the smallest full agonist at the human Y2 receptor

Novel analogues of neuropeptide Y with a preference for the Y1‐receptor

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Modified, cyclic dodecapeptide analog of neuropeptide Y is the smallest full agonist at the human Y₂ receptor

Novel analogues of neuropeptide Y with a preference for the Y₁‐receptor