Molecular recognition of the NPY hormone family by their receptors

Lindner, Diana; Stichel, Jan; Beck‐Sickinger, Annette G.

doi:10.1016/j.nut.2008.06.025

Cited by 64 publications

(63 citation statements)

References 37 publications

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“…NPY signals via a diverse class of G-protein-coupled receptor subtypes, designated Y1, Y2, Y4, Y5, and Y6 (for review, see Lindner et al (2008). Levels of hypothalamic NPY are indicative of nutritional status; NPY mRNA content and NPY release increase during fasting and decrease after refeeding (Sanacora et al, 1990;Swart et al, 2001Swart et al, , 2002.…”

Section: Arcuate Nucleus Orexigenic Neuropeptide Y/agouti-related Pepmentioning

confidence: 99%

Targeting Intermediary Metabolism in the Hypothalamus as a Mechanism to Regulate Appetite

2010

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Section: Arcuate Nucleus Orexigenic Neuropeptide Y/agouti-related Pepmentioning

confidence: 99%

Targeting Intermediary Metabolism in the Hypothalamus as a Mechanism to Regulate Appetite

2010

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“…PYY infusions in pigs yielding near physiological concentrations showed PYY to be degraded COOH terminally to PYY , which was not active on the Y2 receptor, and the peptide was degraded with a half-life (t ½ ) of 3.6 min (35). Studies of NPY-Y1/Y2 receptor interactions showed that an intact COOH-terminal pentapeptide is crucial for the binding and activation of the receptors (27). The COOH-terminal pentapeptides are identical in PYY and NPY, indicating that COOHterminal degradation of PYY will attenuate or ameliorate the binding to and activation of the Y2 receptor.…”

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confidence: 99%

In vivo and in vitro degradation of peptide YY_3–36 to inactive peptide YY_3–34 in humans

Toräng

Bojsen‐Møller

Svane

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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-Peptide YY (PYY) is a 36-amino-acid peptide released from enteroendocrine cells upon food intake. The NH 2 terminally truncated metabolite, PYY3-36, exerts anorexic effects and has received considerable attention as a possible antiobesity drug target. The kinetics and degradation products of PYY metabolism are not well described. A related peptide, neuropeptide Y, may be degraded from the COOH terminus, and in vivo studies in pigs revealed significant COOH-terminal degradation of PYY. We therefore investigated PYY metabolism in vitro after incubation in human blood and plasma and in vivo after infusion of PYY 1-36 and PYY3-36 in eight young, healthy men. A metabolite, corresponding to PYY 3-34, was formed after incubation in plasma and blood and during the infusion of PYY. PYY 3-34 exhibited no agonistic or antagonistic effects on the Y2 receptor. PYY 1-36 infused with and without coadministration of sitagliptin was eliminated with half-lives of 10.1 Ϯ 0.5 and 9.4 Ϯ 0.8 min (means Ϯ SE) and metabolic clearance rates of 15.7 Ϯ 1.5 and 14.1 Ϯ 1.1 ml·kg Ϫ1 ·min Ϫ1 after infusion, whereas PYY 3-36 was eliminated with a significantly longer half-life of 14.9 Ϯ 1.3 min and a metabolic clearance rate of 9.4 Ϯ 0.6 ml·kg Ϫ1 ·min Ϫ1 . We conclude that, upon intravenous infusion in healthy men, PYY is inactivated by cleavage of the two COOHterminal amino acids. In healthy men, PYY 3-36 has a longer half-life than PYY 1-36. peptide YY; kinetics; degradation PEPTIDE YY (PYY) is a gastrointestinal peptide hormone, released into the circulation in response to food intake (3,4,8,18), belonging to the pancreatic polypeptide family together with neuropeptide Y (NPY) and pancreatic polypeptide. These are all 36-amino-acid peptides characterized by a high content of tyrosine, proline, and arginine and a hairpin structure, the so-called " 21).PYY is synthesized and released from endocrine L-cells in the intestinal mucosa, often together with proglugacon-derived peptides, namely glucagon-like peptide-1 (GLP-1), GLP-2, oxyntomodulin, and glicentin. PYY immunoreactive cells are found primarily in ileum and colon with increasing density distally (4).PYY is present in plasma in two major molecular forms, the 36-amino-acid form, PYY 1-36 , and the 34-amino-acid NH 2 -terminally truncated form, PYY 3-36 , which is formed by cleavage of the two NH 2 -terminal amino acids by the enzyme dipeptidyl peptidase-4 (DPP-4) (28). DPP-4 is present in both a soluble form and as a transmembrane protein in endothelial, epithelial, and lymphoid tissue. DPP-4 cleaves and inactivates, e.g., glucose-dependent insulinotropic polypeptide and GLP-1 with short plasma half-lives of 5 and 1-2 min, respectively (15,23,36).Anorexigenic effects of PYY 3-36 have been demonstrated in several studies with intravenous administration of PYY 3-36 (6, 16, 32, 34), whereas infusions of PYY 1-36 have no effect on food intake (34), suggesting that the cleavage of PYY 1-36 to PYY 3-36 is not as complete and rapid as for GLP-1 (34). The half-life of PYY 1-36 has been deter...

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“…YRs together with their three native ligands, NPY, pancreatic polypeptide (PP), and peptide YY (PYY), form a multiligand/ multireceptor system (8), which is involved in many important physiological processes, such as regulation of food intake (9), control of blood pressure, and regulation of pancreatic and gastric secretion (10). The Y 2 R is predominantly expressed as a 381-amino acid protein in the brain cortex (11,12), hippocampus, intestine, and certain blood vessels (8,13,14) and is involved in the inhibition of neurotransmitter release (15), regulation of memory retention (16), circadian rhythm, and angiogenesis (13), which makes it an attractive target for drug development. Potent Y 2 R agonists were suggested as therapy for epilepsy, because Y 2 R selective ligands have been shown to reduce epileptic seizures (17).…”

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Ligand-induced Internalization and Recycling of the Human Neuropeptide Y2 Receptor Is Regulated by Its Carboxyl-terminal Tail

Walther

Nagel

Giménez

et al. 2010

Journal of Biological Chemistry

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Agonist-induced internalization of G protein-coupled receptors plays an important role in signal regulation. The underlying mechanisms of the internalization of the human neuropeptide Y 2 receptor (hY 2 R), as well as its desensitization, endocytosis, and resensitization are mainly unknown. In the present study we have investigated the role of carboxyl-terminal (C-terminal) Ser/Thr residues and acidic amino acids in regulating receptor internalization, arrestin interaction, and recycling by fluorescence microscopy, cell surface enzymelinked immunosorbent assay, and bioluminescence resonance energy transfer in several cell lines. Strikingly, C-terminal truncation mutants revealed two different internalization motifs. Whereas a distal motif 373 DSXTEXT 379 was found to be the primary regulatory internalization sequence acting in concert with arrestin-3, the proximal motif 347 DXXXSEX-SXT 356 promoted ligand-induced internalization in an arrestin-3-independent manner. Moreover, we identified a regulatory sequence located between these internalization motifs ( 357 FKAKKNLEVRKN 368 ), which serves as an inhibitory element. We found that hY 2 R recycling is also governed by structural determinants within the proximal internalization motif. In conclusion, these results indicate that the hY 2 R C terminus is involved in multiple molecular events that regulate internalization, interaction with arrestin-3, and receptor resensitization. Our findings provide novel insights into complex mechanisms of controlled internalization of hY 2 R, which is likely applicable to other GPCRs. G protein-coupled receptors (GPCRs)2 constitute the largest family of cell-surface receptors with ϳ800 known human subtypes. Members of this family share a common architecture of seven membrane-spanning ␣-helices connected by extra-and intracellular loops. GPCRs can be activated by a wide variety of extracellular stimuli and regulate diverse physiological processes (1). Because they are responsible for a multitude of cellular responses and their dysfunction can result in many diseases (2-4), this receptor family represents highly important pharmaceutical targets. More than one-third of the currently available therapeutics act on GPCRs (1). Whereas antagonists mainly prevent receptor interactions with endogenous ligands, agonist drugs might lead to distinct effects in addition to receptor activation, e.g. functional antagonism by receptor removal from the surface (5), direct intracellular cross-signaling (6), and may behave as biased ligands (7). Current information about the complex intracellular network of GPCRs regulation is rather limited. Therefore, it is of great interest to unravel the mechanisms and regulation modalities of receptor internalization and subsequent resensitization processes.The Y 2 R is one of four human neuropeptide Y (NPY) receptor subtypes (hY 1 R, hY 2 R, hY 4 R, and hY 5 R) and belongs to the rhodopsin-like superfamily (class A) of GPCRs. YRs together with their three native ligands, NPY, pancreatic polypeptide (PP), and p...

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Molecular recognition of the NPY hormone family by their receptors

Cited by 64 publications

References 37 publications

Targeting Intermediary Metabolism in the Hypothalamus as a Mechanism to Regulate Appetite

Targeting Intermediary Metabolism in the Hypothalamus as a Mechanism to Regulate Appetite

In vivo and in vitro degradation of peptide YY_3–36 to inactive peptide YY_3–34 in humans

Ligand-induced Internalization and Recycling of the Human Neuropeptide Y2 Receptor Is Regulated by Its Carboxyl-terminal Tail

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Molecular recognition of the NPY hormone family by their receptors

Cited by 64 publications

References 37 publications

Targeting Intermediary Metabolism in the Hypothalamus as a Mechanism to Regulate Appetite

Targeting Intermediary Metabolism in the Hypothalamus as a Mechanism to Regulate Appetite

In vivo and in vitro degradation of peptide YY3–36 to inactive peptide YY3–34 in humans

Ligand-induced Internalization and Recycling of the Human Neuropeptide Y2 Receptor Is Regulated by Its Carboxyl-terminal Tail

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In vivo and in vitro degradation of peptide YY_3–36 to inactive peptide YY_3–34 in humans