title: Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells.
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.
authors: Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark ; Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark.
authors: Maja S
authors: MS
authors: Engelstoft
authors: Won-Mee
authors: WM
authors: Park
authors: Ichiro
authors: I
authors: Sakata
authors: Line V
authors: LV
authors: Kristensen
authors: Anna Sofie
authors: AS
authors: Husted
authors: Sherri
authors: S
authors: Osborne-Lawrence
authors: Paul K
authors: PK
authors: Piper
authors: Angela K
authors: AK
authors: Walker
authors: Maria H
authors: MH
authors: Pedersen
authors: Mark K
authors: MK
authors: Nøhr
authors: Jie
authors: J
authors: Pan
authors: Christopher J
authors: CJ
authors: Sinz
authors: Paul E
authors: PE
authors: Carrington
authors: Taro E
authors: TE
authors: Akiyama
authors: Robert M
authors: RM
authors: Jones
authors: Cong
authors: C
authors: Tang
authors: Kashan
authors: K
authors: Ahmed
authors: Stefan
authors: S
authors: Offermanns
authors: Kristoffer L
authors: KL
authors: Egerod
authors: Jeffrey M
authors: JM
authors: Zigman
authors: Thue W
authors: TW
authors: Schwartz
keywords: 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; Enteroendocrine; G protein signaling; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide 1; GPCR; Ghrelin; Metabolites; PTx, Bordetella pertussis toxin; PYY, peptide YY; Secretion; hrGFP, humanized Renilla reniformis green fluorescent protein