Gq and Gs signaling acting in synergy to control GLP-1 secretion

Mol Cell Endocrinol. 2017 Jul 5:449:64-73. doi: 10.1016/j.mce.2016.11.024. Epub 2016 Nov 28.

Abstract

GPR40 is generally known to signal through Gq. However, in transfected cells, certain synthetic agonists can make the receptor signal also through Gs and cAMP (Hauge et al., 2015). Here we find that, in colonic crypt cultures, the GLP-1 secretion induced by such Gq + Gs GPR40 agonists is indeed inhibited by blockers of both Gq and Gs and is eliminated by combining these. This in contrast to Gq-only GPR40 agonists which only are affected by the Gq inhibitor. Importantly, Gq-only GPR40 agonists in combination with low doses of selective synthetic agonists for Gs coupled receptors, e.g. GPR119 and TGR5 provide more than additive GLP-1 secretion both ex vivo and in vivo in mice. It is concluded that under physiological circumstances triglyceride metabolites, i.e. long chain fatty acids and 2-monoacyl glycerol plus bile acids, act synergistically through their respective receptors, GPR40, GPR119 and TGR5 to stimulate GLP-1 secretion robustly by combining Gq and Gs signaling pathways.

Keywords: G protein signaling; GLP-1 secretion; GPCR; Incretins; Pharmacological synergy.

MeSH terms

  • Administration, Oral
  • Animals
  • Colon / metabolism
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism*
  • GTP-Binding Protein alpha Subunits, Gs / metabolism*
  • Glucagon-Like Peptide 1 / metabolism*
  • Mice, Inbred C57BL
  • Signal Transduction*

Substances

  • Glucagon-Like Peptide 1
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • GTP-Binding Protein alpha Subunits, Gs