FFAR3_HUMAN
ID FFAR3_HUMAN Reviewed; 346 AA.
AC O14843; B2RWM8; Q14CM7;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 1.
DT 03-AUG-2022, entry version 165.
DE RecName: Full=Free fatty acid receptor 3;
DE AltName: Full=G-protein coupled receptor 41;
GN Name=FFAR3; Synonyms=GPR41;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9344866; DOI=10.1006/bbrc.1997.7513;
RA Sawzdargo M., George S.R., Nguyen T., Xu S., Kolakowski L.F. Jr.,
RA O'Dowd B.F.;
RT "A cluster of four novel human G protein-coupled receptor genes occurring
RT in close proximity to CD22 gene on chromosome 19q13.1.";
RL Biochem. Biophys. Res. Commun. 239:543-547(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, and Ovary;
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, CHARACTERIZATION OF VARIANT TRP-174, AND TISSUE SPECIFICITY.
RX PubMed=12496283; DOI=10.1074/jbc.m211609200;
RA Brown A.J., Goldsworthy S.M., Barnes A.A., Eilert M.M., Tcheang L.,
RA Daniels D., Muir A.I., Wigglesworth M.J., Kinghorn I., Fraser N.J.,
RA Pike N.B., Strum J.C., Steplewski K.M., Murdock P.R., Holder J.C.,
RA Marshall F.H., Szekeres P.G., Wilson S., Ignar D.M., Foord S.M., Wise A.,
RA Dowell S.J.;
RT "The orphan G protein-coupled receptors GPR41 and GPR43 are activated by
RT propionate and other short chain carboxylic acids.";
RL J. Biol. Chem. 278:11312-11319(2003).
RN [5]
RP FUNCTION, AND CHARACTERIZATION.
RX PubMed=12711604; DOI=10.1074/jbc.m301403200;
RA Le Poul E., Loison C., Struyf S., Springael J.Y., Lannoy V., Decobecq M.E.,
RA Brezillon S., Dupriez V., Vassart G., Van Damme J., Parmentier M.,
RA Detheux M.;
RT "Functional characterization of human receptors for short chain fatty acids
RT and their role in polymorphonuclear cell activation.";
RL J. Biol. Chem. 278:25481-25489(2003).
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF HIS-146; ARG-185;
RP HIS-245 AND ARG-258.
RX PubMed=18801738; DOI=10.1074/jbc.m805601200;
RA Stoddart L.A., Smith N.J., Jenkins L., Brown A.J., Milligan G.;
RT "Conserved polar residues in transmembrane domains V, VI, and VII of free
RT fatty acid receptor 2 and free fatty acid receptor 3 are required for the
RT binding and function of short chain fatty acids.";
RL J. Biol. Chem. 283:32913-32924(2008).
RN [7]
RP POLYMORPHISM, AND VARIANTS ARG-44; CYS-45; TRP-174; VAL-227; VAL-256 AND
RP ASN-346.
RX PubMed=19630535; DOI=10.1089/dna.2009.0916;
RA Liaw C.W., Connolly D.T.;
RT "Sequence polymorphisms provide a common consensus sequence for GPR41 and
RT GPR42.";
RL DNA Cell Biol. 28:555-560(2009).
RN [8]
RP TISSUE SPECIFICITY.
RX PubMed=21518883; DOI=10.1073/pnas.1016088108;
RA Kimura I., Inoue D., Maeda T., Hara T., Ichimura A., Miyauchi S.,
RA Kobayashi M., Hirasawa A., Tsujimoto G.;
RT "Short-chain fatty acids and ketones directly regulate sympathetic nervous
RT system via G protein-coupled receptor 41 (GPR41).";
RL Proc. Natl. Acad. Sci. U.S.A. 108:8030-8035(2011).
RN [9]
RP FUNCTION, AND MUTAGENESIS OF ASP-158.
RX PubMed=23066016; DOI=10.1074/jbc.m112.396259;
RA Hudson B.D., Tikhonova I.G., Pandey S.K., Ulven T., Milligan G.;
RT "Extracellular ionic locks determine variation in constitutive activity and
RT ligand potency between species orthologs of the free fatty acid receptors
RT FFA2 and FFA3.";
RL J. Biol. Chem. 287:41195-41209(2012).
CC -!- FUNCTION: G protein-coupled receptor that is activated by a major
CC product of dietary fiber digestion, the short chain fatty acids
CC (SCFAs), and that plays a role in the regulation of whole-body energy
CC homeostasis and in intestinal immunity. In omnivorous mammals, the
CC short chain fatty acids acetate, propionate and butyrate are produced
CC primarily by the gut microbiome that metabolizes dietary fibers. SCFAs
CC serve as a source of energy but also act as signaling molecules. That G
CC protein-coupled receptor is probably coupled to the pertussis toxin-
CC sensitive, G(i/o)-alpha family of G proteins. Its activation results in
CC the formation of inositol 1,4,5-trisphosphate, the mobilization of
CC intracellular calcium, the phosphorylation of the MAPK3/ERK1 and
CC MAPK1/ERK2 kinases and the inhibition of intracellular cAMP
CC accumulation (PubMed:12711604). Activated by SCFAs and by beta-
CC hydroxybutyrate, a ketone body produced by the liver upon starvation,
CC it inhibits N-type calcium channels and modulates the activity of
CC sympathetic neurons through a signaling cascade involving the beta and
CC gamma subunits of its coupled G protein, phospholipase C and MAP
CC kinases. Thereby, it may regulate energy expenditure through the
CC control of the sympathetic nervous system that controls for instance
CC heart rate. Upon activation by SCFAs accumulating in the intestine, it
CC may also signal to the brain via neural circuits which in turn would
CC regulate intestinal gluconeogenesis. May also control the production of
CC hormones involved in whole-body energy homeostasis. May for instance,
CC regulate blood pressure through renin secretion. May also regulate
CC secretion of the PYY peptide by enteroendocrine cells and control gut
CC motility, intestinal transit rate, and the harvesting of energy from
CC SCFAs produced by gut microbiota. May also indirectly regulate the
CC production of LEP/Leptin, a hormone acting on the CNS to inhibit food
CC intake, in response to the presence of short-chain fatty acids in the
CC intestine. Finally, may also play a role in glucose homeostasis.
CC Besides its role in energy homeostasis, may play a role in intestinal
CC immunity. May mediate the activation of the inflammatory and immune
CC response by SCFAs in the gut, regulating the rapid production of
CC chemokines and cytokines by intestinal epithelial cells. Among SCFAs,
CC the fatty acids containing less than 6 carbons, the most potent
CC activators are probably propionate, butyrate and pentanoate while
CC acetate is a poor activator (PubMed:12496283, PubMed:12711604).
CC {ECO:0000269|PubMed:12496283, ECO:0000269|PubMed:12711604,
CC ECO:0000269|PubMed:18801738, ECO:0000269|PubMed:23066016}.
CC -!- INTERACTION:
CC O14843; P11912: CD79A; NbExp=3; IntAct=EBI-17762181, EBI-7797864;
CC O14843; P21964: COMT; NbExp=3; IntAct=EBI-17762181, EBI-372265;
CC O14843; Q4LDR2: CTXN3; NbExp=3; IntAct=EBI-17762181, EBI-12019274;
CC O14843; P52803: EFNA5; NbExp=3; IntAct=EBI-17762181, EBI-1753674;
CC O14843; Q9Y2W7: KCNIP3; NbExp=3; IntAct=EBI-17762181, EBI-751501;
CC O14843; O43561-2: LAT; NbExp=3; IntAct=EBI-17762181, EBI-8070286;
CC O14843; Q16873: LTC4S; NbExp=3; IntAct=EBI-17762181, EBI-12241118;
CC O14843; Q9NRX5: SERINC1; NbExp=3; IntAct=EBI-17762181, EBI-2683145;
CC O14843; Q8IVJ1: SLC41A1; NbExp=3; IntAct=EBI-17762181, EBI-12266234;
CC O14843; Q9Y6I9: TEX264; NbExp=3; IntAct=EBI-17762181, EBI-10329860;
CC O14843; Q96B49: TOMM6; NbExp=3; IntAct=EBI-17762181, EBI-10826510;
CC O14843; Q9NSU2-1: TREX1; NbExp=3; IntAct=EBI-17762181, EBI-16746122;
CC O14843; Q9H1C4: UNC93B1; NbExp=3; IntAct=EBI-17762181, EBI-4401271;
CC O14843; Q9Y548: YIPF1; NbExp=3; IntAct=EBI-17762181, EBI-7850136;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:18801738};
CC Multi-pass membrane protein {ECO:0000269|PubMed:18801738}.
CC -!- TISSUE SPECIFICITY: Highest level in adipose tissue, and lower
CC expression across all tissues tested. Expressed in sympathetic ganglia.
CC {ECO:0000269|PubMed:12496283, ECO:0000269|PubMed:21518883}.
CC -!- POLYMORPHISM: The 6 amino acid differences at positions 44, 45, 174,
CC 227, 256 and 346 between GPR42 and FFAR3, are polymorphic in the human
CC population. The frequency of the probable inactive allele of FFAR3,
CC with a Trp at position 174 was estimated to 1%.
CC {ECO:0000269|PubMed:19630535}.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
CC {ECO:0000255|PROSITE-ProRule:PRU00521}.
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DR EMBL; AF024688; AAB86711.1; -; Genomic_DNA.
DR EMBL; U62631; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC035657; AAH35657.1; -; mRNA.
DR EMBL; BC113695; AAI13696.1; -; mRNA.
DR EMBL; BC148269; AAI48270.1; -; mRNA.
DR CCDS; CCDS12459.1; -.
DR PIR; JC5715; JC5715.
DR RefSeq; NP_005295.1; NM_005304.4.
DR AlphaFoldDB; O14843; -.
DR SMR; O14843; -.
DR BioGRID; 109123; 15.
DR IntAct; O14843; 14.
DR STRING; 9606.ENSP00000328230; -.
DR BindingDB; O14843; -.
DR ChEMBL; CHEMBL5201; -.
DR GuidetoPHARMACOLOGY; 227; -.
DR SwissLipids; SLP:000001557; -.
DR GlyGen; O14843; 1 site.
DR BioMuta; FFAR3; -.
DR PaxDb; O14843; -.
DR PeptideAtlas; O14843; -.
DR PRIDE; O14843; -.
DR Antibodypedia; 55509; 184 antibodies from 27 providers.
DR DNASU; 2865; -.
DR Ensembl; ENST00000327809.5; ENSP00000328230.3; ENSG00000185897.7.
DR Ensembl; ENST00000594310.1; ENSP00000469522.1; ENSG00000185897.7.
DR GeneID; 2865; -.
DR KEGG; hsa:2865; -.
DR MANE-Select; ENST00000327809.5; ENSP00000328230.3; NM_005304.5; NP_005295.1.
DR UCSC; uc002nzd.4; human.
DR CTD; 2865; -.
DR DisGeNET; 2865; -.
DR GeneCards; FFAR3; -.
DR HGNC; HGNC:4499; FFAR3.
DR HPA; ENSG00000185897; Tissue enhanced (adipose tissue, breast, lymphoid tissue).
DR MIM; 603821; gene.
DR neXtProt; NX_O14843; -.
DR OpenTargets; ENSG00000185897; -.
DR PharmGKB; PA28888; -.
DR VEuPathDB; HostDB:ENSG00000185897; -.
DR eggNOG; ENOG502QQGM; Eukaryota.
DR GeneTree; ENSGT00990000203527; -.
DR HOGENOM; CLU_009579_8_4_1; -.
DR InParanoid; O14843; -.
DR OMA; HWLYFSV; -.
DR OrthoDB; 1129026at2759; -.
DR PhylomeDB; O14843; -.
DR TreeFam; TF350010; -.
DR PathwayCommons; O14843; -.
DR Reactome; R-HSA-416476; G alpha (q) signalling events.
DR Reactome; R-HSA-444209; Free fatty acid receptors.
DR SignaLink; O14843; -.
DR SIGNOR; O14843; -.
DR BioGRID-ORCS; 2865; 13 hits in 991 CRISPR screens.
DR GeneWiki; Free_fatty_acid_receptor_3; -.
DR GenomeRNAi; 2865; -.
DR Pharos; O14843; Tchem.
DR PRO; PR:O14843; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; O14843; protein.
DR Bgee; ENSG00000185897; Expressed in blood and 79 other tissues.
DR ExpressionAtlas; O14843; baseline and differential.
DR Genevisible; O14843; HS.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0004930; F:G protein-coupled receptor activity; IDA:UniProtKB.
DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW.
DR GO; GO:0007193; P:adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0071398; P:cellular response to fatty acid; IDA:UniProtKB.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0002385; P:mucosal immune response; ISS:UniProtKB.
DR GO; GO:0045776; P:negative regulation of blood pressure; ISS:UniProtKB.
DR GO; GO:0002879; P:positive regulation of acute inflammatory response to non-antigenic stimulus; ISS:UniProtKB.
DR GO; GO:0032722; P:positive regulation of chemokine production; ISS:UniProtKB.
DR GO; GO:0002720; P:positive regulation of cytokine production involved in immune response; ISS:UniProtKB.
DR GO; GO:0046885; P:regulation of hormone biosynthetic process; ISS:UniProtKB.
DR GO; GO:0046626; P:regulation of insulin receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0014061; P:regulation of norepinephrine secretion; ISS:UniProtKB.
DR GO; GO:0090276; P:regulation of peptide hormone secretion; ISS:UniProtKB.
DR InterPro; IPR000276; GPCR_Rhodpsn.
DR InterPro; IPR017452; GPCR_Rhodpsn_7TM.
DR InterPro; IPR013312; GPR40-rel_orph.
DR Pfam; PF00001; 7tm_1; 1.
DR PRINTS; PR00237; GPCRRHODOPSN.
DR PRINTS; PR01904; GPR40FAMILY.
DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1.
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 Immunity; Inflammatory response; Lipid-binding; Membrane; Receptor;
KW Reference proteome; Transducer; Transmembrane; Transmembrane helix.
FT CHAIN 1..346
FT /note="Free fatty acid receptor 3"
FT /id="PRO_0000069569"
FT TOPO_DOM 1..19
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 20..40
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 41..47
FT /note="Cytoplasmic"
FT TRANSMEM 48..68
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 69..88
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 89..111
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 112..132
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 133..153
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 154..178
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 179..199
FT /note="Helical; Name=5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 200..222
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 223..243
FT /note="Helical; Name=6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 244..258
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 259..279
FT /note="Helical; Name=7"
FT /evidence="ECO:0000255"
FT TOPO_DOM 280..346
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 307..346
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 309..329
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 166
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 88..169
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00521"
FT VARIANT 44
FT /note="Q -> R (in dbSNP:rs382771)"
FT /evidence="ECO:0000269|PubMed:19630535"
FT /id="VAR_062854"
FT VARIANT 45
FT /note="R -> C (in dbSNP:rs1359000742)"
FT /evidence="ECO:0000269|PubMed:19630535"
FT /id="VAR_062855"
FT VARIANT 174
FT /note="R -> W (abolishes activation by propionate;
FT dbSNP:rs1415955990)"
FT /evidence="ECO:0000269|PubMed:12496283,
FT ECO:0000269|PubMed:19630535"
FT /id="VAR_062856"
FT VARIANT 227
FT /note="L -> V (in dbSNP:rs1395869674)"
FT /evidence="ECO:0000269|PubMed:19630535"
FT /id="VAR_062857"
FT VARIANT 256
FT /note="A -> V (in dbSNP:rs1170582382)"
FT /evidence="ECO:0000269|PubMed:19630535"
FT /id="VAR_062858"
FT VARIANT 346
FT /note="S -> N (in dbSNP:rs201080710)"
FT /evidence="ECO:0000269|PubMed:19630535"
FT /id="VAR_062962"
FT MUTAGEN 146
FT /note="H->A: Partial loss of SCFA-induced G protein-coupled
FT receptor activity."
FT /evidence="ECO:0000269|PubMed:18801738"
FT MUTAGEN 158
FT /note="D->N: Gain of SCFA-independent constitutive G
FT protein-coupled receptor activity."
FT /evidence="ECO:0000269|PubMed:23066016"
FT MUTAGEN 185
FT /note="R->A: Loss of SCFA-induced G protein-coupled
FT receptor activity."
FT /evidence="ECO:0000269|PubMed:18801738"
FT MUTAGEN 245
FT /note="H->A: Loss of SCFA-induced G protein-coupled
FT receptor activity."
FT /evidence="ECO:0000269|PubMed:18801738"
FT MUTAGEN 258
FT /note="R->A: Loss of SCFA-induced G protein-coupled
FT receptor activity."
FT /evidence="ECO:0000269|PubMed:18801738"
SQ SEQUENCE 346 AA; 38649 MW; B3B19D62D11B6BA1 CRC64;
MDTGPDQSYF SGNHWFVFSV YLLTFLVGLP LNLLALVVFV GKLQRRPVAV DVLLLNLTAS
DLLLLLFLPF RMVEAANGMH WPLPFILCPL SGFIFFTTIY LTALFLAAVS IERFLSVAHP
LWYKTRPRLG QAGLVSVACW LLASAHCSVV YVIEFSGDIS HSQGTNGTCY LEFRKDQLAI
LLPVRLEMAV VLFVVPLIIT SYCYSRLVWI LGRGGSHRRQ RRVAGLLAAT LLNFLVCFGP
YNVSHVVGYI CGESPAWRIY VTLLSTLNSC VDPFVYYFSS SGFQADFHEL LRRLCGLWGQ
WQQESSMELK EQKGGEEQRA DRPAERKTSE HSQGCGTGGQ VACAES
