NameFree fatty acid receptor 2
Synonyms
  • FFA2
  • G-protein coupled receptor 43
  • GPCR43
  • GPR43
Gene NameFFAR2
OrganismHuman
Amino acid sequence
>lcl|BSEQ0013914|Free fatty acid receptor 2
MLPDWKSSLILMAYIIIFLTGLPANLLALRAFVGRIRQPQPAPVHILLLSLTLADLLLLL
LLPFKIIEAASNFRWYLPKVVCALTSFGFYSSIYCSTWLLAGISIERYLGVAFPVQYKLS
RRPLYGVIAALVAWVMSFGHCTIVIIVQYLNTTEQVRSGNEITCYENFTDNQLDVVLPVR
LELCLVLFFIPMAVTIFCYWRFVWIMLSQPLVGAQRRRRAVGLAVVTLLNFLVCFGPYNV
SHLVGYHQRKSPWWRSIAVVFSSLNASLDPLLFYFSSSVVRRAFGRGLQVLRNQGSSLLG
RRGKDTAEGTNEDRGVGQGEGMPSSDFTTE
Number of residues330
Molecular Weight37143.375
Theoretical pINot Available
GO Classification
Functions
  • lipid binding
  • G-protein coupled receptor activity
Processes
  • regulation of acute inflammatory response
  • regulation of peptide hormone secretion
  • glucose homeostasis
  • G-protein coupled receptor signaling pathway
  • positive regulation of chemokine production
  • positive regulation of interleukin-8 secretion
  • cellular response to fatty acid
  • cell surface pattern recognition receptor signaling pathway
  • fat cell differentiation
  • leukocyte chemotaxis involved in inflammatory response
  • lipid storage
  • mucosal immune response
  • positive regulation of acute inflammatory response to non-antigenic stimulus
  • positive regulation of cytokine production involved in immune response
Components
  • plasma membrane
  • integral component of plasma membrane
  • cell projection
General FunctionLipid binding
Specific FunctionG protein-coupled receptor that is activated by a major product of dietary fiber digestion, the short chain fatty acids (SCFAs), and that plays a role in the regulation of whole-body energy homeostasis and in intestinal immunity. In omnivorous mammals, the short chain fatty acids acetate, propionate and butyrate are produced primarily by the gut microbiome that metabolizes dietary fibers. SCFAs serve as a source of energy but also act as signaling molecules. That G protein-coupled receptor is probably coupled to the pertussis toxin-sensitive, G(i/o)-alpha family of G proteins but also to the Gq family (PubMed:12496283, PubMed:12711604, PubMed:23589301). Its activation results in the formation of inositol 1,4,5-trisphosphate, the mobilization of intracellular calcium, the phosphorylation of the MAPK3/ERK1 and MAPK1/ERK2 kinases and the inhibition of intracellular cAMP accumulation. May play a role in glucose homeostasis by regulating the secretion of GLP-1, in response to short-chain fatty acids accumulating in the intestine. May also regulate the production of LEP/Leptin, a hormone acting on the central nervous system to inhibit food intake. Finally, may also regulate whole-body energy homeostasis through adipogenesis regulating both differentiation and lipid storage of adipocytes. In parallel to its role in energy homeostasis, may also mediate the activation of the inflammatory and immune responses by SCFA in the intestine, regulating the rapid production of chemokines and cytokines. May also play a role in the resolution of the inflammatory response and control chemotaxis in neutrophils. In addition to SCFAs, may also be activated by the extracellular lectin FCN1 in a process leading to activation of monocytes and inducing the secretion of interleukin-8/IL-8 in response to the presence of microbes (PubMed:21037097). Among SCFAs, the fatty acids containing less than 6 carbons, the most potent activators are probably acetate, propionate and butyrate (PubMed:12496283, PubMed:12711604). Exhibits a SCFA-independent constitutive G protein-coupled receptor activity (PubMed:23066016).
Pfam Domain Function
Transmembrane Regions13-33 42-62 85-105 127-147 174-194 220-240 256-276
GenBank Protein IDNot Available
UniProtKB IDO15552
UniProtKB Entry NameFFAR2_HUMAN
Cellular LocationCell membrane
Gene sequence
>lcl|BSEQ0013915|Free fatty acid receptor 2 (FFAR2)
ATGCTGCCGGACTGGAAGAGCTCCTTGATCCTCATGGCTTACATCATCATCTTCCTCACT
GGCCTCCCTGCCAACCTCCTGGCCCTGCGGGCCTTTGTGGGGCGGATCCGCCAGCCCCAG
CCTGCACCTGTGCACATCCTCCTGCTGAGCCTGACGCTGGCCGACCTCCTCCTGCTGCTG
CTGCTGCCCTTCAAGATCATCGAGGCTGCGTCGAACTTCCGCTGGTACCTGCCCAAGGTC
GTCTGCGCCCTCACGAGTTTTGGCTTCTACAGCAGCATCTACTGCAGCACGTGGCTCCTG
GCGGGCATCAGCATCGAGCGCTACCTGGGAGTGGCTTTCCCCGTGCAGTACAAGCTCTCC
CGCCGGCCTCTGTATGGAGTGATTGCAGCTCTGGTGGCCTGGGTTATGTCCTTTGGTCAC
TGCACCATCGTGATCATCGTTCAATACTTGAACACGACTGAGCAGGTCAGAAGTGGCAAT
GAAATTACCTGCTACGAGAACTTCACCGATAACCAGTTGGACGTGGTGCTGCCCGTGCGG
CTGGAGCTGTGCCTGGTGCTCTTCTTCATCCCCATGGCAGTCACCATCTTCTGCTACTGG
CGTTTTGTGTGGATCATGCTCTCCCAGCCCCTTGTGGGGGCCCAGAGGCGGCGCCGAGCC
GTGGGGCTGGCTGTGGTGACGCTGCTCAATTTCCTGGTGTGCTTCGGACCTTACAACGTG
TCCCACCTGGTGGGGTATCACCAGAGAAAAAGCCCCTGGTGGCGGTCAATAGCCGTGGTG
TTCAGTTCACTCAACGCCAGTCTGGACCCCCTGCTCTTCTATTTCTCTTCTTCAGTGGTG
CGCAGGGCATTTGGGAGAGGGCTGCAGGTGCTGCGGAATCAGGGCTCCTCCCTGTTGGGA
CGCAGAGGCAAAGACACAGCAGAGGGGACAAATGAGGACAGGGGTGTGGGTCAAGGAGAA
GGGATGCCAAGTTCGGACTTCACTACAGAGTAG
GenBank Gene IDNot Available
GeneCard IDNot Available
GenAtlas IDNot Available
HGNC IDHGNC:4501
Chromosome Location19
LocusNot Available
References
  1. Sawzdargo M, George SR, Nguyen T, Xu S, Kolakowski LF, O'Dowd BF: 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 Oct 20;239(2):543-7. 9344866
  2. Grimwood J, Gordon LA, Olsen A, Terry A, Schmutz J, Lamerdin J, Hellsten U, Goodstein D, Couronne O, Tran-Gyamfi M, Aerts A, Altherr M, Ashworth L, Bajorek E, Black S, Branscomb E, Caenepeel S, Carrano A, Caoile C, Chan YM, Christensen M, Cleland CA, Copeland A, Dalin E, Dehal P, Denys M, Detter JC, Escobar J, Flowers D, Fotopulos D, Garcia C, Georgescu AM, Glavina T, Gomez M, Gonzales E, Groza M, Hammon N, Hawkins T, Haydu L, Ho I, Huang W, Israni S, Jett J, Kadner K, Kimball H, Kobayashi A, Larionov V, Leem SH, Lopez F, Lou Y, Lowry S, Malfatti S, Martinez D, McCready P, Medina C, Morgan J, Nelson K, Nolan M, Ovcharenko I, Pitluck S, Pollard M, Popkie AP, Predki P, Quan G, Ramirez L, Rash S, Retterer J, Rodriguez A, Rogers S, Salamov A, Salazar A, She X, Smith D, Slezak T, Solovyev V, Thayer N, Tice H, Tsai M, Ustaszewska A, Vo N, Wagner M, Wheeler J, Wu K, Xie G, Yang J, Dubchak I, Furey TS, DeJong P, Dickson M, Gordon D, Eichler EE, Pennacchio LA, Richardson P, Stubbs L, Rokhsar DS, Myers RM, Rubin EM, Lucas SM: The DNA sequence and biology of human chromosome 19. Nature. 2004 Apr 1;428(6982):529-35. 15057824
  3. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. 15489334
  4. Nilsson NE, Kotarsky K, Owman C, Olde B: Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochem Biophys Res Commun. 2003 Apr 18;303(4):1047-52. 12684041
  5. Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, Muir AI, Wigglesworth MJ, Kinghorn I, Fraser NJ, Pike NB, Strum JC, Steplewski KM, Murdock PR, Holder JC, Marshall FH, Szekeres PG, Wilson S, Ignar DM, Foord SM, Wise A, Dowell SJ: The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem. 2003 Mar 28;278(13):11312-9. Epub 2002 Dec 19. 12496283
  6. Le Poul E, Loison C, Struyf S, Springael JY, Lannoy V, Decobecq ME, Brezillon S, Dupriez V, Vassart G, Van Damme J, Parmentier M, Detheux M: Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J Biol Chem. 2003 Jul 11;278(28):25481-9. Epub 2003 Apr 23. 12711604
  7. Stoddart LA, Smith NJ, Jenkins L, Brown AJ, Milligan G: Conserved polar residues in transmembrane domains V, VI, and VII of free fatty acid receptor 2 and free fatty acid receptor 3 are required for the binding and function of short chain fatty acids. J Biol Chem. 2008 Nov 21;283(47):32913-24. doi: 10.1074/jbc.M805601200. Epub 2008 Sep 18. 18801738
  8. Swaminath G, Jaeckel P, Guo Q, Cardozo M, Weiszmann J, Lindberg R, Wang Y, Schwandner R, Li Y: Allosteric rescuing of loss-of-function FFAR2 mutations. FEBS Lett. 2010 Oct 8;584(19):4208-14. doi: 10.1016/j.febslet.2010.09.007. Epub 2010 Sep 17. 20837008
  9. Zhang J, Yang L, Ang Z, Yoong SL, Tran TT, Anand GS, Tan NS, Ho B, Ding JL: Secreted M-ficolin anchors onto monocyte transmembrane G protein-coupled receptor 43 and cross talks with plasma C-reactive protein to mediate immune signaling and regulate host defense. J Immunol. 2010 Dec 1;185(11):6899-910. doi: 10.4049/jimmunol.1001225. Epub 2010 Oct 29. 21037097
  10. Swaminath G, Jaeckel P, Guo Q, Cardozo M, Weiszmann J, Lindberg R, Wang Y, Schwandner R, Li Y: Mutational analysis of G-protein coupled receptor--FFA2. Biochem Biophys Res Commun. 2011 Feb 4;405(1):122-7. doi: 10.1016/j.bbrc.2010.12.139. Epub 2011 Jan 7. 21216233
  11. Hudson BD, Tikhonova IG, Pandey SK, Ulven T, Milligan G: Extracellular ionic locks determine variation in constitutive activity and ligand potency between species orthologs of the free fatty acid receptors FFA2 and FFA3. J Biol Chem. 2012 Nov 30;287(49):41195-209. doi: 10.1074/jbc.M112.396259. Epub 2012 Oct 12. 23066016
  12. Hudson BD, Due-Hansen ME, Christiansen E, Hansen AM, Mackenzie AE, Murdoch H, Pandey SK, Ward RJ, Marquez R, Tikhonova IG, Ulven T, Milligan G: Defining the molecular basis for the first potent and selective orthosteric agonists of the FFA2 free fatty acid receptor. J Biol Chem. 2013 Jun 14;288(24):17296-312. doi: 10.1074/jbc.M113.455337. Epub 2013 Apr 15. 23589301