Gq and Gs signaling acting in synergy to control GLP-1 secretion. (5th July 2017)

• Record Type: Journal Article
• Authors: Hauge, Maria; Ekberg, Jeppe Pio; Engelstoft, Maja Storm; Timshel, Pascal; Madsen, Andreas N.; Schwartz, Thue W.
• Is Part Of: Molecular and cellular endocrinology. Volume 449(2017)
• Page Start: 64
• Page End: 73
• Publication Date: 2017-07-05
• Subjects: GPCR -- GLP-1 secretion -- Pharmacological synergy -- Incretins -- G protein signaling; 2-MAG 2-monoacylglycerol -- BB2 bombesin 2 receptor -- CTX cholera toxin -- GLP-1 glucagon-like peptide 1 -- GIP gastrointestinal peptide -- GPCR G protein coupled receptor -- LCFA long chain fatty acid -- NMC neuromedin C -- PLC phospholipase C -- Rim2 Rab3-interacting molecule -- T2D type 2 diabetes; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2016.11.024
• Languages: English
• ISSNs: 0303-7207

Abstract

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. Highlights: Gq and Gs acts in synergy to stimulate GLP-1 secretion. Under fat digestion both Gq and Gs pathways are activated simultaneously through the receptors GPR40, GPR119 and TGR5. The synergistis effect is not seen for the other incretin hormone GIP, indicating a differential secretion pattern between the two cell types.