FFAR1_MOUSE
ID FFAR1_MOUSE Reviewed; 300 AA.
AC Q76JU9; A2RS88; Q8K3T5;
DT 21-MAR-2006, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 125.
DE RecName: Full=Free fatty acid receptor 1;
DE AltName: Full=G-protein coupled receptor 40;
GN Name=Ffar1; Synonyms=Gpr40;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND TISSUE SPECIFICITY.
RC STRAIN=BALB/cJ;
RX PubMed=12496284; DOI=10.1074/jbc.m211495200;
RA Briscoe C.P., Tadayyon M., Andrews J.L., Benson W.G., Chambers J.K.,
RA Eilert M.M., Ellis C., Elshourbagy N.A., Goetz A.S., Minnick D.T.,
RA Murdock P.R., Sauls H.R. Jr., Shabon U., Spinage L.D., Strum J.C.,
RA Szekeres P.G., Tan K.B., Way J.M., Ignar D.M., Wilson S., Muir A.I.;
RT "The orphan G protein-coupled receptor GPR40 is activated by medium and
RT long-chain fatty acids.";
RL J. Biol. Chem. 278:11303-11311(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION.
RX PubMed=12629551; DOI=10.1038/nature01478;
RA Itoh Y., Kawamata Y., Harada M., Kobayashi M., Fujii R., Fukusumi S.,
RA Ogi K., Hosoya M., Tanaka Y., Uejima H., Tanaka H., Maruyama M., Satoh R.,
RA Okubo S., Kizawa H., Komatsu H., Matsumura F., Noguchi Y., Shinohara T.,
RA Hinuma S., Fujisawa Y., Fujino M.;
RT "Free fatty acids regulate insulin secretion from pancreatic beta cells
RT through GPR40.";
RL Nature 422:173-176(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=16044321; DOI=10.1007/s00441-005-0017-z;
RA Salehi A., Flodgren E., Nilsson N.E., Jimenez-Feltstrom J., Miyazaki J.,
RA Owman C., Olde B.;
RT "Free fatty acid receptor 1 (FFA(1)R/GPR40) and its involvement in fatty-
RT acid-stimulated insulin secretion.";
RL Cell Tissue Res. 322:207-215(2005).
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=17395749; DOI=10.2337/db06-1532;
RA Latour M.G., Alquier T., Oseid E., Tremblay C., Jetton T.L., Luo J.,
RA Lin D.C., Poitout V.;
RT "GPR40 is necessary but not sufficient for fatty acid stimulation of
RT insulin secretion in vivo.";
RL Diabetes 56:1087-1094(2007).
RN [6]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=18559658; DOI=10.2337/db08-0553;
RA Kebede M., Alquier T., Latour M.G., Semache M., Tremblay C., Poitout V.;
RT "The fatty acid receptor GPR40 plays a role in insulin secretion in vivo
RT after high-fat feeding.";
RL Diabetes 57:2432-2437(2008).
RN [7]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=23335512; DOI=10.1074/jbc.m112.429084;
RA Wauquier F., Philippe C., Leotoing L., Mercier S., Davicco M.J.,
RA Lebecque P., Guicheux J., Pilet P., Miot-Noirault E., Poitout V.,
RA Alquier T., Coxam V., Wittrant Y.;
RT "The free fatty acid receptor G protein-coupled receptor 40 (GPR40)
RT protects from bone loss through inhibition of osteoclast differentiation.";
RL J. Biol. Chem. 288:6542-6551(2013).
RN [8]
RP FUNCTION, ACTIVITY REGULATION, AND DISRUPTION PHENOTYPE.
RX PubMed=23403053; DOI=10.1016/j.mce.2013.01.009;
RA Xiong Y., Swaminath G., Cao Q., Yang L., Guo Q., Salomonis H., Lu J.,
RA Houze J.B., Dransfield P.J., Wang Y., Liu J.J., Wong S., Schwandner R.,
RA Steger F., Baribault H., Liu L., Coberly S., Miao L., Zhang J., Lin D.C.,
RA Schwarz M.;
RT "Activation of FFA1 mediates GLP-1 secretion in mice. Evidence for
RT allosterism at FFA1.";
RL Mol. Cell. Endocrinol. 369:119-129(2013).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, AND ACTIVITY REGULATION.
RX PubMed=24130766; DOI=10.1371/journal.pone.0076280;
RA Yabuki C., Komatsu H., Tsujihata Y., Maeda R., Ito R., Matsuda-Nagasumi K.,
RA Sakuma K., Miyawaki K., Kikuchi N., Takeuchi K., Habata Y., Mori M.;
RT "A novel antidiabetic drug, fasiglifam/TAK-875, acts as an ago-allosteric
RT modulator of FFAR1.";
RL PLoS ONE 8:E76280-E76280(2013).
CC -!- FUNCTION: G-protein coupled receptor for medium and long chain
CC saturated and unsaturated fatty acids that plays an important role in
CC glucose homeostasis. Fatty acid binding increases glucose-stimulated
CC insulin secretion, and may also enhance the secretion of glucagon-like
CC peptide 1 (GLP-1). May also play a role in bone homeostasis; receptor
CC signaling activates pathways that inhibit osteoclast differentiation
CC (PubMed:23335512). Ligand binding leads to a conformation change that
CC triggers signaling via G-proteins that activate phospholipase C,
CC leading to an increase of the intracellular calcium concentration.
CC Seems to act through a G(q) and G(i)-mediated pathway. Mediates the
CC anti-inflammatory effects of omega-3 polyunsaturated fatty acids
CC (PUFAs) via inhibition of NLRP3 inflammasome activation.
CC {ECO:0000250|UniProtKB:O14842, ECO:0000269|PubMed:12629551,
CC ECO:0000269|PubMed:16044321, ECO:0000269|PubMed:17395749,
CC ECO:0000269|PubMed:18559658, ECO:0000269|PubMed:23335512,
CC ECO:0000269|PubMed:23403053, ECO:0000269|PubMed:24130766}.
CC -!- ACTIVITY REGULATION: Is also activated by synthetic agonists, such as
CC AM-8182, AM-6331 and TAK-875 (fasiglifam). AM-8182 is a full agonist,
CC while AM-6331 and TAK-875 (fasiglifam) are partial agonists that
CC potentiate the activity of the endogenous ligands, such as alpha-
CC linolenic acid and gamma-linolenic acid. {ECO:0000269|PubMed:23403053,
CC ECO:0000269|PubMed:24130766}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:16044321,
CC ECO:0000269|PubMed:24130766}; Multi-pass membrane protein
CC {ECO:0000255}.
CC -!- TISSUE SPECIFICITY: Expressed in pancreatic islet beta cells (at
CC protein level) (PubMed:16044321). Expressed in pancreatic islet beta
CC cells. {ECO:0000269|PubMed:12496284, ECO:0000269|PubMed:16044321}.
CC -!- DISRUPTION PHENOTYPE: No visible phenotype at birth and during the
CC following six weeks. Male mice tend to develop a slightly decreased
CC glucose tolerance after 13 weeks of age, but this is not observed with
CC female mice. Insulin secretion in response to glucose is unchanged in
CC mutant mice, but it is not potentiated by fatty acids, contrary to what
CC is observed with wild-type mice. On the other hand, wild-type and
CC mutant mice display the same inhibition of the first phase of glucose-
CC stimulated insulin secretion after prolonged exposure to fatty acids or
CC exposure to a high-fat diet (PubMed:17395749 and PubMed:18559658).
CC Compared to wild-type, mutant mice that are kept on a high-fat diet
CC display a decrease of the second phase of glucose-stimulated insulin
CC secretion (PubMed:18559658). Mutant mice do not display increased
CC secretion of glucagon-like peptide 1 (GLP-1) in response to oral
CC absorption of corn oil and display slightly increased blood glucose
CC levels after oral absorption of corn oil (PubMed:23403053). Besides,
CC mutant mice display decreased bone density (PubMed:23335512).
CC {ECO:0000269|PubMed:17395749, ECO:0000269|PubMed:18559658,
CC ECO:0000269|PubMed:23335512, ECO:0000269|PubMed:23403053}.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
CC {ECO:0000255|PROSITE-ProRule:PRU00521}.
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DR EMBL; AF539809; AAN03478.1; -; Genomic_DNA.
DR EMBL; AB095745; BAC82555.1; -; mRNA.
DR EMBL; BC132014; AAI32015.1; -; mRNA.
DR EMBL; BC138099; AAI38100.1; -; mRNA.
DR CCDS; CCDS21113.1; -.
DR RefSeq; NP_918946.2; NM_194057.2.
DR AlphaFoldDB; Q76JU9; -.
DR SMR; Q76JU9; -.
DR STRING; 10090.ENSMUSP00000055564; -.
DR BindingDB; Q76JU9; -.
DR ChEMBL; CHEMBL5411; -.
DR GlyGen; Q76JU9; 1 site.
DR iPTMnet; Q76JU9; -.
DR PhosphoSitePlus; Q76JU9; -.
DR PaxDb; Q76JU9; -.
DR PRIDE; Q76JU9; -.
DR Antibodypedia; 15908; 337 antibodies from 34 providers.
DR DNASU; 233081; -.
DR Ensembl; ENSMUST00000052700; ENSMUSP00000055564; ENSMUSG00000044453.
DR GeneID; 233081; -.
DR KEGG; mmu:233081; -.
DR UCSC; uc009ggq.1; mouse.
DR CTD; 2864; -.
DR MGI; MGI:2684079; Ffar1.
DR VEuPathDB; HostDB:ENSMUSG00000044453; -.
DR eggNOG; ENOG502QVCS; Eukaryota.
DR GeneTree; ENSGT00990000203527; -.
DR HOGENOM; CLU_009579_8_4_1; -.
DR InParanoid; Q76JU9; -.
DR OMA; CWRKLGL; -.
DR OrthoDB; 1074213at2759; -.
DR PhylomeDB; Q76JU9; -.
DR TreeFam; TF350010; -.
DR Reactome; R-MMU-381771; Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1).
DR Reactome; R-MMU-400511; Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP).
DR Reactome; R-MMU-416476; G alpha (q) signalling events.
DR Reactome; R-MMU-434316; Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion.
DR Reactome; R-MMU-444209; Free fatty acid receptors.
DR BioGRID-ORCS; 233081; 4 hits in 72 CRISPR screens.
DR PRO; PR:Q76JU9; -.
DR Proteomes; UP000000589; Chromosome 7.
DR RNAct; Q76JU9; protein.
DR Bgee; ENSMUSG00000044453; Expressed in islet of Langerhans and 7 other tissues.
DR GO; GO:0005887; C:integral component of plasma membrane; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0045125; F:bioactive lipid receptor activity; IDA:UniProtKB.
DR GO; GO:0005504; F:fatty acid binding; ISO:MGI.
DR GO; GO:0004930; F:G protein-coupled receptor activity; IBA:GO_Central.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; ISO:MGI.
DR GO; GO:0042593; P:glucose homeostasis; IMP:UniProtKB.
DR GO; GO:0030073; P:insulin secretion; IMP:MGI.
DR GO; GO:0032691; P:negative regulation of interleukin-1 beta production; ISO:MGI.
DR GO; GO:0051928; P:positive regulation of calcium ion transport; IDA:UniProtKB.
DR GO; GO:0010524; P:positive regulation of calcium ion transport into cytosol; ISO:MGI.
DR GO; GO:0007204; P:positive regulation of cytosolic calcium ion concentration; ISS:UniProtKB.
DR GO; GO:0032024; P:positive regulation of insulin secretion; IMP:UniProtKB.
DR GO; GO:0070542; P:response to fatty acid; IDA:UniProtKB.
DR InterPro; IPR000276; GPCR_Rhodpsn.
DR InterPro; IPR017452; GPCR_Rhodpsn_7TM.
DR InterPro; IPR013312; GPR40-rel_orph.
DR InterPro; IPR013313; GPR40_recept_FA.
DR Pfam; PF00001; 7tm_1; 1.
DR PRINTS; PR01905; FATTYACIDR.
DR PRINTS; PR00237; GPCRRHODOPSN.
DR PRINTS; PR01904; GPR40FAMILY.
DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Disulfide bond; G-protein coupled receptor; Glycoprotein;
KW Lipid-binding; Membrane; Receptor; Reference proteome; Transducer;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1..300
FT /note="Free fatty acid receptor 1"
FT /id="PRO_0000227755"
FT TOPO_DOM 1..8
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:O14842, ECO:0000255"
FT TRANSMEM 9..31
FT /note="Helical; Name=1"
FT /evidence="ECO:0000250|UniProtKB:O14842, ECO:0000255"
FT TOPO_DOM 32..41
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:O14842, ECO:0000255"
FT TRANSMEM 42..64
FT /note="Helical; Name=2"
FT /evidence="ECO:0000250|UniProtKB:O14842, ECO:0000255"
FT TOPO_DOM 65..79
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:O14842, ECO:0000255"
FT TRANSMEM 80..101
FT /note="Helical; Name=3"
FT /evidence="ECO:0000250|UniProtKB:O14842, ECO:0000255"
FT TOPO_DOM 102..121
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:O14842, ECO:0000255"
FT TRANSMEM 122..142
FT /note="Helical; Name=4"
FT /evidence="ECO:0000250|UniProtKB:O14842, ECO:0000255"
FT TOPO_DOM 143..178
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:O14842, ECO:0000255"
FT TRANSMEM 179..200
FT /note="Helical; Name=5"
FT /evidence="ECO:0000250|UniProtKB:O14842, ECO:0000255"
FT TOPO_DOM 201..223
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:O14842, ECO:0000255"
FT TRANSMEM 224..248
FT /note="Helical; Name=6"
FT /evidence="ECO:0000250|UniProtKB:O14842, ECO:0000255"
FT TOPO_DOM 249..256
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:O14842, ECO:0000255"
FT TRANSMEM 257..279
FT /note="Helical; Name=7"
FT /evidence="ECO:0000250|UniProtKB:O14842, ECO:0000255"
FT TOPO_DOM 280..300
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:O14842, ECO:0000255"
FT SITE 145
FT /note="Important for receptor activation"
FT /evidence="ECO:0000250|UniProtKB:O14842"
FT SITE 172
FT /note="Important for receptor activation"
FT /evidence="ECO:0000250|UniProtKB:O14842"
FT CARBOHYD 153
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 79..170
FT /evidence="ECO:0000250|UniProtKB:O14842"
FT CONFLICT 7
FT /note="L -> F (in Ref. 1; AAN03478)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 300 AA; 31804 MW; D7FE133E510C399A CRC64;
MDLPPQLSFA LYVSAFALGF PLNLLAIRGA VSHAKLRLTP SLVYTLHLGC SDLLLAITLP
LKAVEALASG AWPLPLPFCP VFALAHFAPL YAGGGFLAAL SAGRYLGAAF PFGYQAIRRP
RYSWGVCVAI WALVLCHLGL ALGLETSGSW LDNSTSSLGI NIPVNGSPVC LEAWDPDSAR
PARLSFSILL FFLPLVITAF CYVGCLRALV RSGLSHKRKL RAAWVAGGAL LTLLLCLGPY
NASNVASFIN PDLGGSWRKL GLITGAWSVV LNPLVTGYLG TGPGRGTICV TRTQRGTIQK
