Free fatty acid receptor 1

UniProt O14842 Organism Homo sapiens Gene FFAR1, GPR40

Also known as: FFAR1, GPR40

Function

G protein-coupled receptor for medium and long chain saturated and unsaturated fatty acids that plays an important role in glucose homeostasis. Fatty acid binding increases glucose-stimulated insulin secretion, and may also enhance the secretion of glucagon-like peptide 1 (GLP-1). May also play a role in bone homeostasis; receptor signaling activates pathways that inhibit osteoclast differentiation (By similarity). Ligand binding leads to a conformation change that triggers signaling via G proteins that activate phospholipase C, leading to an increase of the intracellular calcium concentration. Seems to act through a G(q) and G(i)-mediated pathway. Mediates the anti-inflammatory effects of omega-3 polyunsaturated fatty acids (PUFAs) via inhibition of NLRP3 inflammasome activation.

Classification

Family (Pfam): PF00001 7tm_1
InterPro: GPCR_Rhodpsn, GPCR_Rhodpsn_7TM, GPR40-rel_orph, GPR40_recept_FA
Functional cluster: G Protein-Coupled Receptors

Experimental structures · PDB · 9

4PHU X-ray 2.33A
5KW2 X-ray 2.76A
5TZR X-ray 2.20A
5TZY X-ray 3.22A
8EIT EM 2.80A
8EJC EM 3.00A
8EJK EM 3.40A
8T3V EM 3.39A
9K1C EM 3.20A

A predicted model is available from AlphaFold.

Gene Ontology · 11

Drugs targeting this protein · 3

FASIGLIFAM positive allosteric modulator
LY2881835 agonist
SETOGEPRAM agonist

Related proteins · sequence + function similarity

Co-cited proteins · studied together in the literature

Free fatty acid receptor 1 2 shared papers
Free fatty acid receptor 1 1 shared papers
Free fatty acid receptor 4 2 shared papers
G protein-coupled receptor 42 1 shared papers
Free fatty acid receptor 4 1 shared papers
Free fatty acid receptor 3 1 shared papers
Free fatty acid receptor 2 1 shared papers
NACHT, LRR and PYD domains-containing protein 3 1 shared papers
Beta-arrestin-2 1 shared papers
NACHT, LRR and PYD domains-containing protein 3 1 shared papers

Literature · 12 cited papers

Structural basis for GPR40 allosteric agonism and incretin stimulation. Nat. Commun. · 2018
High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. Nature · 2014
Alteration of the glucagon axis in GPR120 (FFAR4) knockout mice: a role for GPR120 in glucagon secretion. J. Biol. Chem. · 2014
A novel antidiabetic drug, fasiglifam/TAK-875, acts as an ago-allosteric modulator of FFAR1. PLoS ONE · 2013
Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity · 2013
Phytanic acid and pristanic acid, branched-chain fatty acids associated with Refsum disease and other inherited peroxisomal disorders, mediate intracellular Ca2+ signaling through activation of free fatty acid receptor GPR40. Neurobiol. Dis. · 2011
Two arginine-glutamate ionic locks near the extracellular surface of FFAR1 gate receptor activation. J. Biol. Chem. · 2009
Identification of residues important for agonist recognition and activation in GPR40. J. Biol. Chem. · 2007
GPR40 gene expression in human pancreas and insulinoma. Biochem. Biophys. Res. Commun. · 2005
The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
The orphan G protein-coupled receptor GPR40 is activated by medium and long-chain fatty acids. J. Biol. Chem. · 2003
A cluster of four novel human G protein-coupled receptor genes occurring in close proximity to CD22 gene on chromosome 19q13.1. Biochem. Biophys. Res. Commun. · 1997

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