期刊
MOLECULAR METABOLISM
卷 2, 期 4, 页码 376-392出版社
ELSEVIER
DOI: 10.1016/j.molmet.2013.08.006
关键词
Ghrelin; GPCR; Enteroendocrine; Secretion; G protein signaling; Metabolites
资金
- Novo Nordisk Foundation
- UNIK project for Food, Fitness & Pharma from Danish Ministry of Science, Technology and Innovation
- Lundbeck Foundation
- Danish Medical Research Council
- Faculty of Heath and Medical Sciences, University of Copenhagen
- Endocrine Fellows Foundation
- NIH [T32DA7290]
- EMBO
- Grants-in-Aid for Scientific Research [24790941] Funding Source: KAKEN
The molecular mechanisms regulating secretion of the orexigenic-glucoregulatory hormone ghrelin remain unclear. Based on qPCR analysis of FACS-purified gastric ghrelin cells, highly expressed and enriched 7TM receptors were comprehensively identified and functionally characterized using in vitro, ex vivo and in vivo methods. Five Gas-coupled receptors efficiently stimulated ghrelin secretion: as expected the beta 1-adrenergic, the GIP and the secretin receptors but surprisingly also the composite receptor for the sensory neuropeptide CGRP and the melanocortin 4 receptor. A number of G alpha i/o-coupled receptors inhibited ghrelin secretion including somatostatin receptors SSTR1, SSTR2 and SSTR3 and unexpectedly the highly enriched lactate receptor, GPR81. Three other metabolite receptors known to be both G alpha i/o- and G alpha q/11-coupled all inhibited ghrelin secretion through a pertussis toxin-sensitive G alpha i/o pathway: FFAR2 (short chain fatty acid receptor; GPR43), FFAR4 (long chain fatty acid receptor; GPR120) and CasR (calcium sensing receptor). In addition to the common G alpha subunits three non-common G alpha i/o subunits were highly enriched in ghrelin cells: G alpha oA, G alpha oB and G alpha z. Inhibition of G alpha i/o signaling via ghrelin cell-selective pertussis toxin expression markedly enhanced circulating ghrelin. These 7TM receptors and associated G alpha subunits constitute a major part of the molecular machinery directly mediating neuronal and endocrine stimulation versus metabolite and somatostatin inhibition of ghrelin secretion including a series of novel receptor targets not previously identified on the ghrelin cell. (C) 2013 The Authors. Published by Elsevier GmbH All rights reserved.
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