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 ampli�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 “guanine nucleotide-binding protein subunit alpha-11� (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.a5fcb2a5fcb2a5fcb2a5fcb2a5fcb2a5fcb2a5fcb2a5fcb2a5fcb2G protein mediated signaling pathwayPW:0000125Pathway Ontologysignaling pathwayPW:0000003Pathway Ontologyinsulin secretion pathwayPW:0000674Pathway Ontology24051395PubMedModulating GPR40: therapeutic promise and potential in diabetes2013Poitout VLin DC23631851PubMedThe fatty acid receptor FFA1/GPR40 a decade later: how much do we know? Mancini AD1, Poitout V.2013Mancini ADPoitout V