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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Maja S Engelstoft
  • Won-Mee Park
  • Ichiro Sakata
  • Line V Kristensen
  • Sherri Osborne-Lawrence
  • Paul K Piper
  • Angela K Walker
  • Jie Pan
  • Christopher J Sinz
  • Paul E Carrington
  • Taro E Akiyama
  • Robert M Jones
  • Cong Tang
  • Kashan Ahmed
  • Stefan Offermanns
  • Jeffrey M Zigman

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.

OriginalsprogEngelsk
TidsskriftMolecular Metabolism
Vol/bind2
Udgave nummer4
Sider (fra-til)376-92
Antal sider17
ISSN2212-8778
DOI
StatusUdgivet - nov. 2013

ID: 117973224