GPR40 pathway (WP3958)

Homo sapiens

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.


Amnah Siddiqa , Egon Willighagen , Alex Pico , Kristina Hanspers , Martina Summer-Kutmon , Friederike Ehrhart , and Eric Weitz


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Homo sapiens



Pathway Ontology

G protein mediated signaling pathway signaling pathway insulin secretion pathway


Label Type Compact URI Comment
inositol-3-phosphate Metabolite chebi:16595
DAG Metabolite chebi:18035
Ca2+ Metabolite chebi:29108
PLCH1 GeneProduct ensembl:ENSG00000114805
PLCD3 GeneProduct ensembl:ENSG00000161714
PLCG2 GeneProduct ensembl:ENSG00000197943
PKD1 GeneProduct ensembl:ENSG00000008710
IP3R GeneProduct ensembl:ENSG00000096433
PLCD1 GeneProduct ensembl:ENSG00000187091
PLCZ1 GeneProduct ensembl:ENSG00000139151
PLCB1 GeneProduct ensembl:ENSG00000182621
GNA11 GeneProduct ensembl:ENSG00000088256
PLCE1 GeneProduct ensembl:ENSG00000138193
PLCL1 GeneProduct ensembl:ENSG00000115896
PLCB2 GeneProduct ensembl:ENSG00000137841
PLCB3 GeneProduct ensembl:ENSG00000149782
GPR40 GeneProduct ensembl:ENSG00000126266
PLCG1 GeneProduct ensembl:ENSG00000124181


  1. 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
  2. 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