GPR40 pathway (WP3958)
G-protein-coupled receptor GPR40 (also known as Free fatty acid receptor 1(FFAR1)) is a seven trans-membrane domain receptor which is predominantly expressed in pancreatic beta cells. It plays an essential role in fatty acid ampliï¬�cation of glucose induced insulin secretion. GPR40 agonists are in second phase of preclinical trials for treatment of diabetes because of their role in improved glucose control. Binding of free fatty acids to GPR40 initiates a downstream signaling cascade which involves activation of a transducer protein â€œguanine nucleotide-binding protein subunit alpha-11â€� (GNA11). Next phospholipase c (PLC) hormone is activated which hydrolyzes membrane phospholipids (such as phosphatidylinositol-4-5-biphosphate) into second messenger molecules inositol-1-4-5-trophosphate (IP3) and Diacylglycerol (DAG). IP3 initiates calcium efflux from endoplasmic reticulum and increase intracellular calcium concentration. Increased intracellular calcium concentration is involved in activating the insulin exocytosis machinery. DAG on the other hand activates PKD1. PKD1 initiates F-actin remodeling and supports second phase of insulin exocytosis.
AuthorsAmnah Siddiqa , Egon Willighagen , Alex Pico , Kristina Hanspers , Martina Summer-Kutmon , Friederike Ehrhart , and Eric Weitz
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Pathway OntologyG protein mediated signaling pathway signaling pathway insulin secretion pathway
- The fatty acid receptor FFA1/GPR40 a decade later: how much do we know? Mancini AD, Poitout V. Trends Endocrinol Metab. 2013 Aug;24(8):398–407. PubMed Europe PMC Scholia
- Modulating GPR40: therapeutic promise and potential in diabetes. Poitout V, Lin DCH. Drug Discov Today. 2013 Dec;18(23–24):1301–8. PubMed Europe PMC Scholia