Y₄ Receptors Mediate the Inhibitory Responses of Pancreatic Polypeptide in Human and Mouse Colon Mucosa

Abstract

ABSTRACT

Towards improved receptor targeting: anterograde transport, internalization and postendocytic trafficking of neuropeptide Y receptors

“…In addition to these findings, the rate of Y 4 receptor sequestration was found to be highly sensitive to agonist affinity and efficacy, i.e., full agonists induced a higher internalization rate than partial agonists (Parker et al , 2002a ;Tough et al , 2006 ). This is in agreement with the common mechanism of GPCR activation followed by sequestration, as described above, and underlines the fact that the endogenous Y 4 ligands generate two conformations, which are equally important for G protein and GRK/ Arr binding.…”

“…Initially, the hY 4 receptor was reported to be resistant to agonistpromoted desensitization and internalization when being expressed in Chinese hamster ovary cells (Voisin et al , 2000 ). In contrast, several other groups independently showed that the Y 4 receptor is rapidly internalized and subsequently transported back to the cell surface, most probably via the indirect recycling pathway (Parker et al , 2001(Parker et al , , 2002aTough et al , 2006 ;Bohme et al , 2008 ). The determined internalization and recycling rates were either comparable or slightly slower than those observed for the Y 1 receptor.…”

“…It is worth noting that GR231118 was initially identified to have agonistic effects only for Y 4 , while displaying a classical antagonistic function towards Y 1 (Schober et al , 1998 ;Dumont and Quirion , 2000 ). In fact, Y 1 receptor internalization induced by GR231118 could not be confirmed in later experiments, even though the receptor species and cell types were consistent with the initial study (Tough et al , 2006 ). One possible explanation for this might be that internalization experiments by Pheng et al were based on the internalization of the radio-labeled GR231118, while later studies focused on receptor redistribution subsequent to ligand stimulation.…”

“…Moreover, the Y 4 receptor inhibits gastric emptying in humans, followed by a delayed postprandial increase in blood glucose levels and subsequent insulin secretion (Schmidt et al , 2005 ), thereby inducing anorexigenic effects. As the Y 4 receptor also has an inhibitory effect on gastrointestinal secretion, it might be a potent target in diarrheal disorders (Tough et al , 2006 ). Besides this, the Y 4 receptor was found to be expressed in several human colon adenocarcinoma cell lines (Cox et al , 2001 ), pointing towards this receptor having a role in the development of colon cancer in humans.…”

Pancreatic Polypeptide Is Recognized by Two Hydrophobic Domains of the Human Y4 Receptor Binding Pocket

“…Physiologically, the Y 4 R is involved in the regulation of food intake (9), colonic anion transport (10), and adipose tissue and bone formation synergistically with Y 2 R (11). The Y 4 R sequence is one of the least conserved members of the NPYR family among different species, making it the fastest evolving functional member of the family (12).…”