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

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. Nøhr, 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. ZigmanThue W. Schwartz

Research output: Contribution to journalArticle

138 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)376-392
Number of pages17
JournalMolecular Metabolism
Volume2
Issue number4
DOIs
StatePublished - Nov 2013

Fingerprint

Ghrelin
Stomach
Pertussis Toxin
Neuropeptide Receptors
Receptor, Melanocortin, Type 4
Ghrelin Receptor
Calcium-Sensing Receptors
seven-transmembrane G-protein-coupled receptor
Somatostatin Receptors
Volatile Fatty Acids
Sensory Receptor Cells
Somatostatin
Adrenergic Agents
Lactic Acid
Fatty Acids
Hormones

Keywords

  • Enteroendocrine
  • G protein signaling
  • Ghrelin
  • GPCR
  • Metabolites
  • Secretion

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Engelstoft, M. S., Park, W. M., Sakata, I., Kristensen, L. V., Husted, A. S., Osborne-Lawrence, S., ... Schwartz, T. W. (2013). Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells. Molecular Metabolism, 2(4), 376-392. https://doi.org/10.1016/j.molmet.2013.08.006

Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells. / Engelstoft, Maja S.; Park, Won mee; Sakata, Ichiro; Kristensen, Line V.; Husted, Anna Sofie; Osborne-Lawrence, Sherri; Piper, Paul K.; Walker, Angela K.; Pedersen, Maria H.; Nøhr, Mark K.; Pan, Jie; Sinz, Christopher J.; Carrington, Paul E.; Akiyama, Taro E.; Jones, Robert M.; Tang, Cong; Ahmed, Kashan; Offermanns, Stefan; Egerod, Kristoffer L.; Zigman, Jeffrey M.; Schwartz, Thue W.

In: Molecular Metabolism, Vol. 2, No. 4, 11.2013, p. 376-392.

Research output: Contribution to journalArticle

Engelstoft, MS, Park, WM, Sakata, I, Kristensen, LV, Husted, AS, Osborne-Lawrence, S, Piper, PK, Walker, AK, Pedersen, MH, Nøhr, MK, Pan, J, Sinz, CJ, Carrington, PE, Akiyama, TE, Jones, RM, Tang, C, Ahmed, K, Offermanns, S, Egerod, KL, Zigman, JM & Schwartz, TW 2013, 'Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells', Molecular Metabolism, vol. 2, no. 4, pp. 376-392. https://doi.org/10.1016/j.molmet.2013.08.006
Engelstoft MS, Park WM, Sakata I, Kristensen LV, Husted AS, Osborne-Lawrence S et al. Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells. Molecular Metabolism. 2013 Nov;2(4):376-392. https://doi.org/10.1016/j.molmet.2013.08.006
Engelstoft, Maja S. ; Park, Won mee ; Sakata, Ichiro ; Kristensen, Line V. ; Husted, Anna Sofie ; Osborne-Lawrence, Sherri ; Piper, Paul K. ; Walker, Angela K. ; Pedersen, Maria H. ; Nøhr, Mark K. ; Pan, Jie ; Sinz, Christopher J. ; Carrington, Paul E. ; Akiyama, Taro E. ; Jones, Robert M. ; Tang, Cong ; Ahmed, Kashan ; Offermanns, Stefan ; Egerod, Kristoffer L. ; Zigman, Jeffrey M. ; Schwartz, Thue W. / Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells. In: Molecular Metabolism. 2013 ; Vol. 2, No. 4. pp. 376-392.
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