GPR142 Agonists Stimulate Glucose-Dependent Insulin Secretion via Gq-Dependent Signaling.
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.
Lilly China Research and Development Center (LCRDC), Eli Lilly & Company, Shanghai, China.
Jingru
J
Wang
Lilly Research Laboratories, Lilly Corporate Center (LCC), Eli Lilly & Company, Indianapolis, IN, United States of America.
Juan J
JJ
Carrillo
Lilly China Research and Development Center (LCRDC), Eli Lilly & Company, Shanghai, China.
Hua V
HV
Lin
D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000819:agonists* / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D061251:Primary Cell Culture; D021122:Protein Subunits / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014364:Tryptophan / Q000494:pharmacology*
D000631:Aminopyridines; C501537:GPR142 protein, human; D007328:Insulin; D021122:Protein Subunits; D011720:Pyrazoles; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; D005576:Colforsin; D014364:Tryptophan; D000242:Cyclic AMP; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D005947:Glucose