title: Gq and Gs signaling acting in synergy to control GLP-1 secretion.
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.
authors.affiliation: NNF Center for Basic Metabolic Research, Section for Metabolic Receptology, 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.forename: Maria
authors.initials: M
authors.lastname: Hauge
authors.affiliation: NNF Center for Basic Metabolic Research, Section for Metabolic Receptology, 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.forename: Jeppe Pio
authors.initials: JP
authors.lastname: Ekberg
authors.affiliation: NNF Center for Basic Metabolic Research, Section for Metabolic Receptology, 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.forename: Maja Storm
authors.initials: MS
authors.lastname: Engelstoft
authors.affiliation: NNF Center for Basic Metabolic Research, Section of Metabolic Genomics, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark.
authors.forename: Pascal
authors.initials: P
authors.lastname: Timshel
authors.affiliation: NNF Center for Basic Metabolic Research, Section for Metabolic Receptology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark.
authors.forename: Andreas N
authors.initials: AN
authors.lastname: Madsen
authors.affiliation: NNF Center for Basic Metabolic Research, Section for Metabolic Receptology, 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. Electronic address: tws@sund.ku.dk.
authors.forename: Thue W
authors.initials: TW
authors.lastname: Schwartz
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003106:Colon / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D015398:Signal Transduction
chemical_list: D052216:Glucagon-Like Peptide 1; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: G protein signaling; GLP-1 secretion; GPCR; Incretins; Pharmacological synergy