Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV

Mentlein, Rolf; Dahms, Peter; Grandt, Daniel; Krüger, Ragna

doi:10.1016/0167-0115(93)90435-b

Cited by 319 publications

(190 citation statements)

References 24 publications

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“…Plasma half-lives of PYY and PYY in rats, and the relative blood-brain barrier permeabilities of each peptide, remain to be determined. The enzyme dipeptidyl-peptidase IV (DPP IV) cleaves the NH 2 -terminal Tyr-Pro of PYY to yield PYY(3-36) (35). DPP IV is located on the endothelial cells of blood vessels as a soluble enzyme in plasma and in a number of other tissues (34).…”

Section: Discussionmentioning

confidence: 99%

Comparison of the inhibitory effects of PYY(3-36) and PYY(1-36) on gastric emptying in rats

Chelikani

Haver²,

Reidelberger³

2004

American Journal of Physiology-Regulatory, Integrative and Comp

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We compared the effects of the two molecular forms of the brain-gut peptide YY (PYY), PYY(1-36) and PYY(3-36), on gastric emptying. Unanesthetized rats received 20-min intravenous infusions of rat PYY(1-36) (0, 1.7, 5, 17, 50, 100, 170 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) and rat PYY(3-36) (0, 0.5, 1.7, 5, 17, 50, 100, 170 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 ), either alone or combined, and gastric emptying of saline was measured during the last 10 min of infusion. For comparison, human PYY(3-36) was administered at 0, 17, and 50 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 . Gastric emptying was decreased by 11, 24, 26 and 38% in response to 17, 50, 100, and 170 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 of rat PYY(1-36); by 10, 26, 41, 53, and 57% in response to 5, 17, 50, 100, and 170 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 of rat PYY(3-36); and by 35 and 53% in response to 17 and 50 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 of human PYY(3-36), respectively. Estimated ED50s were 470 and 37 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 for rat PYY(1-36) and PYY(3-36), respectively. In general, within an experiment, coadministration of PYY(1-36) and PYY(3-36) inhibited gastric emptying by an amount that was comparable to that produced when either peptide was given alone. We conclude that 1) intravenous infusion of PYY(1-36) and PYY(3-36) each produces a dose-dependent inhibition of gastric emptying in rats, 2) PYY(3-36) is an order of magnitude more potent than PYY(1-36) in inhibiting gastric emptying, 3) human PYY(3-36) and rat PYY(3-36) inhibit gastric emptying similarly, and 4) PYY(1-36) and PYY(3-36) do not appear to interact in an additive or synergistic manner to inhibit gastric emptying. intravenous infusion; dose response; interaction PEPTIDE YY (PYY), neuropeptide Y (NPY), and pancreatic polypeptide (PP) comprise the "PP-fold" family of structurally related brain-gut peptides. PYY is synthesized in the gastrointestinal tract, as well as in the central and peripheral nervous systems. Endocrine cells of the ileum, colon, and rectum provide a major source of PYY (2, 47). PYY has also been detected in gastric mucosa, pancreatic islets, myenteric and serosal ganglia, sympathetic neurons, adrenal gland, spinal cord, and brain, including the hypothalamus, pituitary, pons, medulla oblongata, and the brain stem (7-9, 15, 16, 22, 30, 32, 37).Food intake releases PYY into the circulation (2, 47). Systemic administration of PYY inhibits food intake, gastric emptying, intestinal fluid and electrolyte secretion, gallbladder contraction, and exocrine pancreatic secretion (5, 36). Whether PYY acts physiologically by endocrine, neurocrine, and/or paracrine mechanisms to produce these effects remains to be determined. If PYY acts as a blood-borne hormonal signal to produce an effect, then it is important to determine whether the effect is produced by intravenous doses of PYY that reproduce meal-induced increases in plasma PYY.The two major molecular forms of PYY found in the gut and circulation are PYY(1-36) and PYY(3-36) (19 -21). In humans, plasma concentrations of PYY were reported to be 11 pM in the fasted state with PYY(3-36) contributing 37% ...

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Section: Discussionmentioning

confidence: 99%

Comparison of the inhibitory effects of PYY(3-36) and PYY(1-36) on gastric emptying in rats

Chelikani

Haver²,

Reidelberger³

2004

American Journal of Physiology-Regulatory, Integrative and Comp

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“…9 Cleavage by the enzyme dipeptidyl-peptidase IV yields the circulating form most abundant after a meal, PYY . 10,11 In the fasting state, PYY is the dominating form. 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.…”

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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“…Degradation of the peptide and desensitization of the NPY signal have been reported [4,5]. Recently, investigations showed that CHO cells expressing the Y4 receptor were resistant to agonist-promoted desensitization and internalization [6].…”

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confidence: 99%

Monitoring of the internalization of neuropeptide Y on neuroblastoma cell line SK‐N‐MC

Fabry

Langer

Rothen‐Rutishauser

et al. 2000

European Journal of Biochemistry

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Neuropeptide Y (NPY) is an important neuromodulator in the central and peripheral nervous system. The peptide acts through different NPY receptor subtypes (Y1±Y5, y6) that belong to the family of G protein-coupled receptors. In general, cellular responses to prolonged exposure to agonists of G protein-coupled receptors are attenuated, often through internalization of the receptors and their bound ligands. In this study, a fluorescent labeled NPY derivative was synthesized and characterized to investigate the internalization of NPY in the human neuroblastoma cell line SK-N-MC. Internalization was proven by binding experiments and subsequent acidic washing as well as by direct visualization by means of confocal laser scanning microscopy. Approximately 20±30% of the fluorescent labeled NPY and a tritium-marked NPY were resistant to acid removal of cell surfacebound ligands indicating internalization. Extracellular fluorescent labeled NPY was found to be distributed heterogeneously in a clustered pattern, which suggests that the ligand-receptor complex is collected in pits and caveolae followed by endocytosis. Keywords: neuropeptide Y (NPY); internalization; neuroblastoma cells; fluorescent labeling.Neuropeptide Y (NPY) is a neurotransmitter consisting of 36 amino acids that belongs to the family of pancreatic polypeptides. These polypeptides are important modulators of the central and peripheral nervous system and NPY is one of the most abundant neuropeptides in the brain. NPY acts peripherally as a vasoconstrictor and modulates the activity of further neurotransmitters. Centrally, NPY is involved in the stimulating of food intake, memory retention and anxiolysis. So far, five receptor subtypes (Y1, Y2, Y4, Y5, y6) were identified that bind NPY with nanomolar affinity [1]. They all belong to the large family of G protein-coupled receptors (GPCR) with their typical seven-transmembrane helix structure [2].Approximately 80% of all bioactive molecules, especially hormones and neurotransmitters, act through the interaction of GPCR that transduce extracellular signals to the interior of cells. Signaling through these receptors, however, is rapidly desensitized primarily as a consequence of receptor phosphorylation, but internalization and receptor downregulation have also been shown to occur [3]. Many GPCR are known to internalize after agonist binding, however, the conditions for this mechanism and its importance for the desensitization and resensitization as well as for the fate of receptor and ligand within the cells are different and often unclear.Regulatory mechanisms of signal attenuation, including the removal of the ligands from the extracellular space by enzymatic degradation, are important to ensure the ability of the cells to react to the agonists. Degradation of the peptide and desensitization of the NPY signal have been reported [4,5]. Recently, investigations showed that CHO cells expressing the Y4 receptor were resistant to agonist-promoted desensitization and internalization [6].In the present study, we e...

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Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV

Cited by 319 publications

References 24 publications

Comparison of the inhibitory effects of PYY(3-36) and PYY(1-36) on gastric emptying in rats

Comparison of the inhibitory effects of PYY(3-36) and PYY(1-36) on gastric emptying in rats

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

Monitoring of the internalization of neuropeptide Y on neuroblastoma cell line SK‐N‐MC

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