GPR142 Agonists Stimulate Glucose-Dependent Insulin Secretion via Gq-Dependent Signaling

• Published in: PloS one Vol. 11; no. 4; p. e0154452
• Main Authors: Wang, Jingru, Carrillo, Juan J, Lin, Hua V
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22.04.2016; Public Library of Science (PLoS)
• Subjects: Aminopyridines - pharmacology; Animals; Antibiotics; Biology and Life Sciences; Care and treatment; Cloning; Colforsin - pharmacology; Cyclic AMP - metabolism; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); G proteins; Gene Expression Regulation; Glucose; Glucose - metabolism; Glucose - pharmacology; HEK293 Cells; Humans; Insulin; Insulin - agonists; Insulin - metabolism; Insulin Secretion; Islets of Langerhans; Islets of Langerhans - cytology; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Kinases; Male; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Pancreas; Phosphorylation; Physical Sciences; Primary Cell Culture; Protein Subunits - agonists; Protein Subunits - genetics; Protein Subunits - metabolism; Proteins; Pyrazoles - pharmacology; R&D; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Research & development; Rodents; Secretion; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Signaling; Stimulation; Sulfonylureas; Therapeutic applications; Therapeutics; Tryptophan - pharmacology; Type 2 diabetes; United States > US; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0154452

GPR142 is an islet-enriched G protein-coupled receptor that has been investigated as a novel therapeutic target for the treatment of type 2 diabetes by virtue of its insulin secretagogue activity. However, the signaling pathways downstream of GPR142 and whether its stimulation of insulin release is glucose-dependent remain poorly characterized. In this study, we show that both native and synthetic GPR142 agonists can activate Gq as well as Gi signaling when GPR142 is recombinantly expressed in HEK293 cells. However, in primary pancreatic islets, a native cellular system, the insulin secretagogue activity of GPR142 agonists only requires Gq activation. In addition, our results show that stimulation of insulin secretion by GPR142 in pancreatic islets is strictly glucose-dependent.