Molecular Characterization of the Human Neuropeptide Y Y2-Receptor

Ingenhoven, Nikolaus; Eckard, Christophe P.; Gehlert, Donald R.; Beck‐Sickinger, Annette G.

doi:10.1021/bi982831b

Cited by 17 publications

(15 citation statements)

References 41 publications

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“…NPYAc [25][26][27][28][29][30][31][32][33][34][35][36] (cycloNPYAc [25][26][27][28][29][30][31][32][33][34][35][36] ; purity 1 95%). BIE0246 (purity 1 98%) was synthesized at F. Hoffmann-La Roche AG, Basel, Switzerland.…”

Section: Materials Peptides Reagents and Radiochemicalsmentioning

confidence: 99%

“…30% after 24 h) was achieved [Dautzenberg and Higelin, unpubl.]. This quasi-irreversible binding could not be blocked by a variety of NPY analogs including the Y 2 -specifi c agonist NPYcycloAc [25][26][27][28][29][30][31][32][33][34][35][36] [23] and the small molecule Y 2 -antagonist BIIE0246 [14] . The ligands used in this study showed impaired competition binding already after 30 min pre-incubation of the radiolabel, and after pre-incubation for 60 min less than 50% of the radiolabel was displaceable.…”

Section: Insurmountable Antagonism Of Biie0246 After Pre-incubationmentioning

confidence: 99%

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Irreversible Binding Kinetics of Neuropeptide Y Ligands to Y2 but Not to Y1 and Y5 Receptors

Dautzenberg

Neysari

2005

Pharmacology

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Neuropeptide Y (NPY) receptors type 1 (Y₁), type 2 Y₂) and type 5 (Y₅) were tested for their kinetic properties to bind radiolabeled NPY or PYY. Rapid association and dissociation was observed with recombinant (HEK293 cells) and endogenous (SK-N-MC cells) human Y₁ and recombinant mouse Y₅ receptors. Recombinant (HEK293) and endogenous (SMS-KAN) human Y₂ receptors bound both radiolabels comparable to the Y₁ receptors, but only minimal (∼20%) dissociation of both radiolabels was observed after long incubation time (>8 h). Furthermore, neither peptide nor small molecule Y₂ ligands efficiently competed for binding to Y₂ receptors once association binding had been initiated. The Y₂-selective antagonist BIIE0246 behaved as an insurmountable antagonist in functional assays when pre-incubated for 30 min before agonist addition, but was a competitive antagonist when co-applied with the agonist. These data show that Y₂ receptors in contrast to Y₁ and Y₅ receptors bind their ligands in an irreversible manner.

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Section: Materials Peptides Reagents and Radiochemicalsmentioning

confidence: 99%

Section: Insurmountable Antagonism Of Biie0246 After Pre-incubationmentioning

confidence: 99%

Irreversible Binding Kinetics of Neuropeptide Y Ligands to Y2 but Not to Y1 and Y5 Receptors

Dautzenberg

Neysari

2005

Pharmacology

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“…PYY 1–36 binds to and activates all members of the human NPY family of receptors (Y1‐Y5) with equal affinity, all of which are widely distributed throughout the central nervous system (CNS) and peripheral tissues . However, this is not the case for the main circulating form of PYY, PYY 3–36, which is selective for and exhibits highest affinity binding only to the G‐protein coupled Y 2 receptor (Y 2 R) …”

Section: Introductionmentioning

confidence: 99%

Role of Peptide YY in blood vessel function and atherosclerosis in a rabbit model

Smith

Klein

Kružliak

et al. 2015

Clin Exp Pharma Physio

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Cardiovascular disease remains a burden for Westernized countries. Peptide YY (PYY) raises blood pressure, yet its role has not yet been determined in diseased arteries. This study aimed at identifying PYY and eNOS in diseased blood vessels and to determine which blood vessels respond to PYY. New Zealand White rabbits were fed an atherogenic diet (n = 6, 0.5% cholesterol + 1% methionine + 5% peanut oil) and control animals fed a normal diet (n = 6) for 4 weeks. Immunohistochemistry was used to determine the localization of PYY and eNOS in the aorta. The aorta, carotid, renal, iliac, inferior mesenteric, and renal interlobular arteries were removed, mounted in organ baths, and subjected to doses of PYY (10(-9) -10(-7) mol/L) and then acetylcholine (10(-6) mol/L). Immunohistochemistry of the aorta shows PYY staining in plaque macrophages, smooth muscle cells and endothelium, and these cells co-expressed eNOS. PYY caused a minor vasoconstrictive response in all blood vessels studied but was blunted in arteries from control animals. Acetylcholine caused relaxation of PYY constricted blood vessels. This data clearly shows that PYY is present in atherosclerotic plaque and is a minor constrictor of the vasculature tree. Further studies aimed at understanding the role of PYY in cardiovascular disease are warranted.

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“…9 While PYY and NPY 12 can activate NPY receptors Y1, Y2 and Y5, PYY 3-36 is a selective agonist for the Y2 receptor. 13 Y2R is a seven transmembrane domain G-protein-coupled presynaptic inhibitory autoreceptor, 14 which is highly expressed in NPY neurons within the hypothalamic arcuate nucleus, a key brain area regulating appetite. 15 Peripheral and intra-arcuate administration of PYY in rodents inhibits food intake.…”

Section: Introductionmentioning

confidence: 99%

Common neuropeptide Y2 receptor gene variant is protective against obesity among Swedish men

et al. 2005

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Background: Gut hormones and their receptors are considered important in the control of feeding behavior. The gut hormone peptide-YY (PYY) has anorexic effects via the inhibitory neuropeptide Y2 receptor (Y2R) highly expressed in orexigenic NPY/ AGRP neurons within the arcuate nucleus, a major integrator of appetite control in the hypothalamus. Design: Genetic case-control association study of single nucleotide polymorphisms (SNPs) in Y2R and PYY. Subjects: Swedish Caucasians comprising 148 lean, 129 overweight/obese and 226 morbidly obese men. Measurements: Genotypes of the common, silent and conserved SNP Y2R 585T4C and the common SNP PYY Arg72Thr, as well as various obesity-related clinical parameters. Results: Obese men had a lower allele and homozygosity frequency of the common allele 585T4C:T which was particularly evident comparing morbidly obese with lean men (P ¼ 0.002), and analyzing dependence between continuous body mass index (BMI) and genotype (P ¼ 0.002). In agreement, systolic blood pressure tended to be lower in those homozygous for allele T, which was not explained by the BMI -genotype dependence. We found no association to obesity for the PYY Arg72Thr polymorphism, which is located nearby the essential carboxy terminal. Conclusion: A common and conserved variant of the PYY and NPY receptor Y2R is less prevalent among obese compared to among lean Swedish men. This suggests that the common Y2R variant is protective against obesity. Our findings further implicate Y2R in food intake regulation.

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Molecular Characterization of the Human Neuropeptide Y Y₂-Receptor

Cited by 17 publications

References 41 publications

Irreversible Binding Kinetics of Neuropeptide Y Ligands to Y<sub>2</sub> but Not to Y<sub>1</sub> and Y<sub>5</sub> Receptors

Irreversible Binding Kinetics of Neuropeptide Y Ligands to Y<sub>2</sub> but Not to Y<sub>1</sub> and Y<sub>5</sub> Receptors

Role of Peptide YY in blood vessel function and atherosclerosis in a rabbit model

Common neuropeptide Y2 receptor gene variant is protective against obesity among Swedish men

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