Elsevier

Molecular Metabolism

Volume 2, Issue 4, November 2013, Pages 376-392
Molecular Metabolism

Original article
Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells

https://doi.org/10.1016/j.molmet.2013.08.006Get rights and content
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Abstract

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 Gαs-coupled receptors efficiently stimulated ghrelin secretion: as expected the β1-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 Gαi/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 Gαi/o- and Gαq/11-coupled all inhibited ghrelin secretion through a pertussis toxin-sensitive Gαi/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 Gα subunits three non-common Gαi/o subunits were highly enriched in ghrelin cells: GαoA, GαoB and Gαz. Inhibition of Gαi/o signaling via ghrelin cell-selective pertussis toxin expression markedly enhanced circulating ghrelin. These 7TM receptors and associated Gα 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.

Abbreviations

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

Keywords

Ghrelin
GPCR
Enteroendocrine
Secretion
G protein signaling
Metabolites

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This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.