FFAR3_MOUSE
ID FFAR3_MOUSE Reviewed; 319 AA.
AC Q3UFD7;
DT 21-MAR-2006, integrated into UniProtKB/Swiss-Prot.
DT 11-OCT-2005, sequence version 1.
DT 03-AUG-2022, entry version 111.
DE RecName: Full=Free fatty acid receptor 3;
DE AltName: Full=G-protein coupled receptor 41;
GN Name=Ffar3; Synonyms=Gm478, Gpr41;
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 [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Sympathetic ganglion;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=14722361; DOI=10.1073/pnas.2637002100;
RA Xiong Y., Miyamoto N., Shibata K., Valasek M.A., Motoike T.,
RA Kedzierski R.M., Yanagisawa M.;
RT "Short-chain fatty acids stimulate leptin production in adipocytes through
RT the G protein-coupled receptor GPR41.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:1045-1050(2004).
RN [3]
RP FUNCTION, DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY.
RX PubMed=18931303; DOI=10.1073/pnas.0808567105;
RA Samuel B.S., Shaito A., Motoike T., Rey F.E., Backhed F., Manchester J.K.,
RA Hammer R.E., Williams S.C., Crowley J., Yanagisawa M., Gordon J.I.;
RT "Effects of the gut microbiota on host adiposity are modulated by the
RT short-chain fatty-acid binding G protein-coupled receptor, Gpr41.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:16767-16772(2008).
RN [4]
RP FUNCTION.
RX PubMed=20399779; DOI=10.1016/j.febslet.2010.04.027;
RA Zaibi M.S., Stocker C.J., O'Dowd J., Davies A., Bellahcene M.,
RA Cawthorne M.A., Brown A.J., Smith D.M., Arch J.R.;
RT "Roles of GPR41 and GPR43 in leptin secretory responses of murine
RT adipocytes to short chain fatty acids.";
RL FEBS Lett. 584:2381-2386(2010).
RN [5]
RP FUNCTION, DISRUPTION PHENOTYPE, TISSUE SPECIFICITY, AND DEVELOPMENTAL
RP STAGE.
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 [6]
RP FUNCTION, DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY.
RX PubMed=22190648; DOI=10.2337/db11-1019;
RA Tolhurst G., Heffron H., Lam Y.S., Parker H.E., Habib A.M.,
RA Diakogiannaki E., Cameron J., Grosse J., Reimann F., Gribble F.M.;
RT "Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via
RT the G-protein-coupled receptor FFAR2.";
RL Diabetes 61:364-371(2012).
RN [7]
RP FUNCTION.
RX PubMed=22673524; DOI=10.1016/j.febslet.2012.04.021;
RA Inoue D., Kimura I., Wakabayashi M., Tsumoto H., Ozawa K., Hara T.,
RA Takei Y., Hirasawa A., Ishihama Y., Tsujimoto G.;
RT "Short-chain fatty acid receptor GPR41-mediated activation of sympathetic
RT neurons involves synapsin 2b phosphorylation.";
RL FEBS Lett. 586:1547-1554(2012).
RN [8]
RP FUNCTION, AND MUTAGENESIS OF ASN-154.
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).
RN [9]
RP DISRUPTION PHENOTYPE.
RX PubMed=23110765; DOI=10.1017/s0007114512003923;
RA Bellahcene M., O'Dowd J.F., Wargent E.T., Zaibi M.S., Hislop D.C.,
RA Ngala R.A., Smith D.M., Cawthorne M.A., Stocker C.J., Arch J.R.;
RT "Male mice that lack the G-protein-coupled receptor GPR41 have low energy
RT expenditure and increased body fat content.";
RL Br. J. Nutr. 109:1755-1764(2013).
RN [10]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=23665276; DOI=10.1053/j.gastro.2013.04.056;
RA Kim M.H., Kang S.G., Park J.H., Yanagisawa M., Kim C.H.;
RT "Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial
RT cells to promote inflammatory responses in mice.";
RL Gastroenterology 145:396-406(2013).
RN [11]
RP FUNCTION.
RX PubMed=23401498; DOI=10.1073/pnas.1215927110;
RA Pluznick J.L., Protzko R.J., Gevorgyan H., Peterlin Z., Sipos A., Han J.,
RA Brunet I., Wan L.X., Rey F., Wang T., Firestein S.J., Yanagisawa M.,
RA Gordon J.I., Eichmann A., Peti-Peterdi J., Caplan M.J.;
RT "Olfactory receptor responding to gut microbiota-derived signals plays a
RT role in renin secretion and blood pressure regulation.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:4410-4415(2013).
RN [12]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=24748202; DOI=10.1371/journal.pone.0095268;
RA Han J.H., Kim I.S., Jung S.H., Lee S.G., Son H.Y., Myung C.S.;
RT "The effects of propionate and valerate on insulin responsiveness for
RT glucose uptake in 3T3-L1 adipocytes and C2C12 myotubes via G protein-
RT coupled receptor 41.";
RL PLoS ONE 9:E95268-E95268(2014).
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. Activated by SCFAs and by beta-hydroxybutyrate, a ketone
CC body produced by the liver upon starvation, it inhibits N-type calcium
CC channels and modulates the activity of sympathetic neurons through a
CC signaling cascade involving the beta and gamma subunits of its coupled
CC G protein, phospholipase C and MAP kinases. Thereby, it may regulate
CC energy expenditure through the control of the sympathetic nervous
CC system that controls for instance heart rate (PubMed:21518883,
CC PubMed:22673524). Upon activation by SCFAs accumulating in the
CC intestine, it may also signal to the brain via neural circuits which in
CC turn would regulate intestinal gluconeogenesis. May also control the
CC production of hormones involved in whole-body energy homeostasis. May
CC for instance, regulate blood pressure through renin secretion
CC (PubMed:23401498). May also regulate secretion of the PYY peptide by
CC enteroendocrine cells and control gut motility, intestinal transit
CC rate, and the harvesting of energy from SCFAs produced by gut
CC microbiota (PubMed:18931303). 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 (PubMed:14722361, PubMed:20399779). Finally, may also play a
CC role in glucose homeostasis (PubMed:22190648, PubMed:24748202). Besides
CC its role in energy homeostasis, may play a role in intestinal immunity.
CC May mediate the activation of the inflammatory and immune response by
CC SCFAs in the gut, regulating the rapid production of chemokines and
CC cytokines by intestinal epithelial cells (PubMed:23665276). Exhibits an
CC SCFA-independent constitutive G protein-coupled receptor activity
CC (PubMed:23066016). {ECO:0000269|PubMed:14722361,
CC ECO:0000269|PubMed:18931303, ECO:0000269|PubMed:20399779,
CC ECO:0000269|PubMed:21518883, ECO:0000269|PubMed:22190648,
CC ECO:0000269|PubMed:22673524, ECO:0000269|PubMed:23066016,
CC ECO:0000269|PubMed:23401498, ECO:0000269|PubMed:23665276,
CC ECO:0000269|PubMed:24748202}.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.
CC -!- TISSUE SPECIFICITY: Expressed in white adipose tissue and skeletal
CC muscle (at protein level). Abundantly expressed in sympathetic ganglia
CC such as the superior cervical ganglion. Also expressed by intestinal
CC endocrine cells. {ECO:0000269|PubMed:14722361,
CC ECO:0000269|PubMed:18931303, ECO:0000269|PubMed:21518883,
CC ECO:0000269|PubMed:22190648, ECO:0000269|PubMed:24748202}.
CC -!- DEVELOPMENTAL STAGE: Expressed in sympathetic ganglia and trunks at
CC 13.5 dpc, 15.5 dpc and P1. Up-regulated during myocyte and adipocyte
CC differentiation (at protein level). {ECO:0000269|PubMed:21518883}.
CC -!- DISRUPTION PHENOTYPE: Knockout mice display a retarded growth of
CC sympathetic innervation and the superior cervical ganglion is
CC significantly smaller. A heart rate decrease is also observed together
CC with altered secretion of cardiac noradrenaline that might be due to
CC reduced sympathetic nerve activity. Contrary to wild-type mice, oxygen
CC consumption is not modified by feeding or starvation (PubMed:21518883).
CC They also display impaired SCFA-triggered glucagon-like peptide 1/GLP-1
CC secretion and impaired glucose tolerance (PubMed:22190648). Finally,
CC knockout mice display altered protective intestinal inflammatory and
CC immune responses. Otherwise, they display normal growth and no major
CC morphological abnormalities. Body weight, heart weight to body weight
CC ratio, and metabolic parameters are comparable. However, there might be
CC a gender bias, the effect on energy expenditure and body fat content
CC being male specific (PubMed:23110765). {ECO:0000269|PubMed:18931303,
CC ECO:0000269|PubMed:21518883, ECO:0000269|PubMed:22190648,
CC ECO:0000269|PubMed:23110765, ECO:0000269|PubMed:23665276}.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
CC {ECO:0000255|PROSITE-ProRule:PRU00521}.
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DR EMBL; AK148616; BAE28624.1; -; mRNA.
DR CCDS; CCDS21112.1; -.
DR RefSeq; NP_001028488.1; NM_001033316.2.
DR AlphaFoldDB; Q3UFD7; -.
DR SMR; Q3UFD7; -.
DR STRING; 10090.ENSMUSP00000092163; -.
DR BindingDB; Q3UFD7; -.
DR ChEMBL; CHEMBL3309101; -.
DR GlyGen; Q3UFD7; 2 sites.
DR PaxDb; Q3UFD7; -.
DR PRIDE; Q3UFD7; -.
DR Ensembl; ENSMUST00000094583; ENSMUSP00000092163; ENSMUSG00000019429.
DR Ensembl; ENSMUST00000185748; ENSMUSP00000140252; ENSMUSG00000019429.
DR GeneID; 233080; -.
DR KEGG; mmu:233080; -.
DR UCSC; uc009ggp.1; mouse.
DR CTD; 2865; -.
DR MGI; MGI:2685324; Ffar3.
DR VEuPathDB; HostDB:ENSMUSG00000019429; -.
DR eggNOG; ENOG502QQGM; Eukaryota.
DR GeneTree; ENSGT00990000203527; -.
DR HOGENOM; CLU_009579_8_4_1; -.
DR InParanoid; Q3UFD7; -.
DR OMA; HWLYFSV; -.
DR OrthoDB; 1129026at2759; -.
DR PhylomeDB; Q3UFD7; -.
DR TreeFam; TF350010; -.
DR Reactome; R-MMU-416476; G alpha (q) signalling events.
DR Reactome; R-MMU-444209; Free fatty acid receptors.
DR BioGRID-ORCS; 233080; 0 hits in 71 CRISPR screens.
DR PRO; PR:Q3UFD7; -.
DR Proteomes; UP000000589; Chromosome 7.
DR RNAct; Q3UFD7; protein.
DR Bgee; ENSMUSG00000019429; Expressed in islet of Langerhans and 17 other tissues.
DR ExpressionAtlas; Q3UFD7; baseline and differential.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0016020; C:membrane; IDA:MGI.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0004930; F:G protein-coupled receptor activity; IDA:MGI.
DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW.
DR GO; GO:0007193; P:adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway; IMP:MGI.
DR GO; GO:0071398; P:cellular response to fatty acid; IMP:UniProtKB.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; IDA:MGI.
DR GO; GO:0042593; P:glucose homeostasis; IMP:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0002385; P:mucosal immune response; IMP:UniProtKB.
DR GO; GO:0045776; P:negative regulation of blood pressure; IMP:UniProtKB.
DR GO; GO:0019228; P:neuronal action potential; IMP:MGI.
DR GO; GO:0002879; P:positive regulation of acute inflammatory response to non-antigenic stimulus; IMP:UniProtKB.
DR GO; GO:0032722; P:positive regulation of chemokine production; IMP:UniProtKB.
DR GO; GO:0002720; P:positive regulation of cytokine production involved in immune response; IMP:UniProtKB.
DR GO; GO:1904457; P:positive regulation of neuronal action potential; IMP:MGI.
DR GO; GO:0003062; P:regulation of heart rate by chemical signal; IMP:MGI.
DR GO; GO:0046885; P:regulation of hormone biosynthetic process; IMP:UniProtKB.
DR GO; GO:0046626; P:regulation of insulin receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0014061; P:regulation of norepinephrine secretion; IMP:UniProtKB.
DR GO; GO:0090276; P:regulation of peptide hormone secretion; IMP: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..319
FT /note="Free fatty acid receptor 3"
FT /id="PRO_0000227783"
FT TOPO_DOM 1..15
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 16..36
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 37..43
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 44..64
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 65..98
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 99..119
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 120..127
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 128..148
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 149..183
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 184..206
FT /note="Helical; Name=5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 207..218
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 219..239
FT /note="Helical; Name=6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 240..254
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 255..275
FT /note="Helical; Name=7"
FT /evidence="ECO:0000255"
FT TOPO_DOM 276..319
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT CARBOHYD 154
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 162
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 84..165
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00521"
FT MUTAGEN 154
FT /note="N->D: Loss of SCFA-independent constitutive G
FT protein-coupled receptor activity."
FT /evidence="ECO:0000269|PubMed:23066016"
SQ SEQUENCE 319 AA; 36501 MW; B049EC4A8BFEDCC4 CRC64;
MGTSFFLGNY WLFFSVYLLV FLVGLPLNVM ALVVFVGKLR RRPVAVDLLL LNLTISDLLL
LLFLPFRMVE AACGMRWLLP FIFCPLSGFL FFTTIYLTSL FLTAVSIERF LSVAYPLWYK
TRPRLAQAGL VSVVCWFLAS AHCSVVYITE YWGNATYSQG TNGTCYLEFR EDQLAILLPV
RLEMAVVLFM VPLCITSYCY SRLVWILSRG ASRRRRKRIM GLLAATLLIF FVCFGPYNMS
HVVGYVSRES PSWRSYVLLL STLNSCIDPL VFYFSSSKFQ ADFHQLLGRL LRTCVPWTQQ
VSLELKVKNG EEPSKECPS
