Free fatty acid receptor 3

Details

Name

Free fatty acid receptor 3

Synonyms

• G-protein coupled receptor 41
• GPR41

Gene Name

FFAR3

Organism

Humans

Amino acid sequence

>lcl|BSEQ0052679|Free fatty acid receptor 3
MDTGPDQSYFSGNHWFVFSVYLLTFLVGLPLNLLALVVFVGKLQRRPVAVDVLLLNLTAS
DLLLLLFLPFRMVEAANGMHWPLPFILCPLSGFIFFTTIYLTALFLAAVSIERFLSVAHP
LWYKTRPRLGQAGLVSVACWLLASAHCSVVYVIEFSGDISHSQGTNGTCYLEFRKDQLAI
LLPVRLEMAVVLFVVPLIITSYCYSRLVWILGRGGSHRRQRRVAGLLAATLLNFLVCFGP
YNVSHVVGYICGESPAWRIYVTLLSTLNSCVDPFVYYFSSSGFQADFHELLRRLCGLWGQ
WQQESSMELKEQKGGEEQRADRPAERKTSEHSQGCGTGGQVACAES

Number of residues

346

Molecular Weight

38648.675

Theoretical pI

Not Available

GO Classification

Functions

G protein-coupled receptor activity / lipid binding

Processes

adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / cellular response to fatty acid / G protein-coupled receptor signaling pathway / inflammatory response / mucosal immune response / negative regulation of blood pressure / positive regulation of acute inflammatory response to non-antigenic stimulus / positive regulation of chemokine production / positive regulation of cytokine production involved in immune response / regulation of hormone biosynthetic process / regulation of insulin receptor signaling pathway / regulation of norepinephrine secretion / regulation of peptide hormone secretion

Components

integral component of plasma membrane / plasma membrane

General Function

G 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. 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 (PubMed:12711604). Activated by SCFAs and by beta-hydroxybutyrate, a ketone body produced by the liver upon starvation, it inhibits N-type calcium channels and modulates the activity of sympathetic neurons through a signaling cascade involving the beta and gamma subunits of its coupled G protein, phospholipase C and MAP kinases. Thereby, it may regulate energy expenditure through the control of the sympathetic nervous system that controls for instance heart rate. Upon activation by SCFAs accumulating in the intestine, it may also signal to the brain via neural circuits which in turn would regulate intestinal gluconeogenesis. May also control the production of hormones involved in whole-body energy homeostasis. May for instance, regulate blood pressure through renin secretion. May also regulate secretion of the PYY peptide by enteroendocrine cells and control gut motility, intestinal transit rate, and the harvesting of energy from SCFAs produced by gut microbiota. May also indirectly regulate the production of LEP/Leptin, a hormone acting on the CNS to inhibit food intake, in response to the presence of short-chain fatty acids in the intestine. Finally, may also play a role in glucose homeostasis. Besides its role in energy homeostasis, may play a role in intestinal immunity. May mediate the activation of the inflammatory and immune response by SCFAs in the gut, regulating the rapid production of chemokines and cytokines by intestinal epithelial cells. Among SCFAs, the fatty acids containing less than 6 carbons, the most potent activators are probably propionate, butyrate and pentanoate while acetate is a poor activator (PubMed:12496283, PubMed:12711604).

Specific Function

G protein-coupled receptor activity

Pfam Domain Function

• 7tm_1 (PF00001)

Transmembrane Regions

20-40 48-68 89-111 133-153 179-199 223-243 259-279

Cellular Location

Cell membrane

Gene sequence

>lcl|BSEQ0052680|Free fatty acid receptor 3 (FFAR3)
ATGGATACAGGCCCCGACCAGTCCTACTTCTCCGGCAATCACTGGTTCGTCTTCTCGGTG
TACCTTCTCACTTTCCTGGTGGGGCTCCCCCTCAACCTGCTGGCCCTGGTGGTCTTCGTG
GGCAAGCTGCAGCGCCGCCCGGTGGCCGTGGACGTGCTCCTGCTCAACCTGACCGCCTCG
GACCTGCTCCTGCTGCTGTTCCTGCCTTTCCGCATGGTGGAGGCAGCCAATGGCATGCAC
TGGCCCCTGCCCTTCATCCTCTGCCCACTCTCTGGATTCATCTTCTTCACCACCATCTAT
CTCACCGCCCTCTTCCTGGCAGCTGTGAGCATTGAACGCTTCCTGAGTGTGGCCCACCCA
CTGTGGTACAAGACCCGGCCGAGGCTGGGGCAGGCAGGTCTGGTGAGTGTGGCCTGCTGG
CTGTTGGCCTCTGCTCACTGCAGCGTGGTCTACGTCATAGAATTCTCAGGGGACATCTCC
CACAGCCAGGGCACCAATGGGACCTGCTACCTGGAGTTCCGGAAGGACCAGCTAGCCATC
CTCCTGCCCGTGCGGCTGGAGATGGCTGTGGTCCTCTTTGTGGTCCCGCTGATCATCACC
AGCTACTGCTACAGCCGCCTGGTGTGGATCCTCGGCAGAGGGGGCAGCCACCGCCGGCAG
AGGAGGGTGGCGGGGCTGTTGGCGGCCACGCTGCTCAACTTCCTTGTCTGCTTTGGGCCC
TACAACGTGTCCCATGTCGTGGGCTATATCTGCGGTGAAAGCCCGGCGTGGAGGATCTAC
GTGACGCTTCTCAGCACCCTGAACTCCTGTGTCGACCCCTTTGTCTACTACTTCTCCTCC
TCCGGGTTCCAAGCCGACTTTCATGAGCTGCTGAGGAGGTTGTGTGGGCTCTGGGGCCAG
TGGCAGCAGGAGAGCAGCATGGAGCTGAAGGAGCAGAAGGGAGGGGAGGAGCAGAGAGCG
GACCGACCAGCTGAAAGAAAGACCAGTGAACACTCACAGGGCTGTGGAACTGGTGGCCAG
GTGGCCTGTGCTGAAAGCTAG

Chromosome Location

19

Locus

19q13.12

External Identifiers

Resource	Link
UniProtKB ID	O14843
UniProtKB Entry Name	FFAR3_HUMAN
HGNC ID	HGNC:4499

General 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. [Article]
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. [Article]
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. [Article]
4. 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. [Article]
5. 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. [Article]
6. 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. [Article]
7. Liaw CW, Connolly DT: Sequence polymorphisms provide a common consensus sequence for GPR41 and GPR42. DNA Cell Biol. 2009 Nov;28(11):555-60. doi: 10.1089/dna.2009.0916. [Article]
8. Kimura I, Inoue D, Maeda T, Hara T, Ichimura A, Miyauchi S, Kobayashi M, Hirasawa A, Tsujimoto G: Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci U S A. 2011 May 10;108(19):8030-5. doi: 10.1073/pnas.1016088108. Epub 2011 Apr 25. [Article]
9. 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. [Article]

Drug Relations

Drug Relations

DrugBank ID	Name	Drug group	Pharmacological action?	Actions	Details