Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells
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- 作者：Maja S. Engelstoft ; Won-mee Park ; Ichiro Sakata ; Line V. Kristensen ; Anna Sofie Husted ; Sherri Osborne-Lawrence ; Paul K. Piper ; Angela K. Walker ; Maria H. Pedersen ; Mark K. N酶hr ; Jie Pan ; Christopher J. Sinz ; Paul E. Carrington ; Taro E. Akiyama ; Robert M. Jones ; Cong Tang ; Kashan Ahmed ; Stefan Offermanns ; Kristoffer L. Egerod ; Jeffrey M. Zigman ; et al.
- 关键词：7TM ; seven transmembrane segment ; BAC ; bacterial artificial chromosome ; CCK ; cholecystokinin ; CFMB ; (S)-2-(4-chlorophenyl)-3 ; 3-dimethyl-N-(5-phenylthiazol-2-yl)butamide ; CGRP ; calcitonin gene-related peptide ; CHBA ; 3-chloro-5-hydroxybenzoic acid ; hrGFP ; humanized Renilla reniformis green fluorescent protein ; GLP-1 ; glucagon-like peptide 1 ; GIP ; glucose-dependent insulinotropic polypeptide ; PTx ; Bordetella pertussis toxin ; PYY ; peptide YY
- 刊名：Molecular Metabolism
- 出版年：November, 2013
- 年：2013
- 卷：2
- 期：4
- 页码：376-392
- 全文大小：2489 K
文摘
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 G伪s-coupled receptors efficiently stimulated ghrelin secretion: as expected the 尾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伪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伪i/o- and G伪q/11-coupled all inhibited ghrelin secretion through a pertussis toxin-sensitive G伪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伪 subunits three non-common G伪i/o subunits were highly enriched in ghrelin cells: G伪oA, G伪oB and G伪z. Inhibition of G伪i/o signaling via ghrelin cell-selective pertussis toxin expression markedly enhanced circulating ghrelin. These 7TM receptors and associated G伪 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.