Contents:
- Gene and Protein Information
- Previous and Unofficial Names
- Database Links
- Natural/Endogenous Ligands
- Agonists
- Antagonists
- Allosteric Modulators
- Immunopharmacology Comments
- Immuno Cell Type Associations
- Immuno Process Associations
- Transduction Mechanisms
- Tissue Distribution
- Expression Datasets
- Functional Assays
- Physiological Functions
- Physiological Consequences of Altering Gene Expression
- Phenotypes, Alleles and Disease Models
- References
- Contributors
- How to cite this page
Gene and Protein Information  |
||||||
| class A G protein-coupled receptor | ||||||
| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 7 | 330 | 19q13.12 | FFAR2 | free fatty acid receptor 2 | 21 |
| Mouse | 7 | 330 | 7 B1 | Ffar2 | free fatty acid receptor 2 | 23 |
| Rat | 7 | 330 | 1q21 | Ffar2 | free fatty acid receptor 2 | 10 |
| Previous and Unofficial Names |
|
| FFA2R | GPCR3 | GPR43 [21] | G protein-coupled receptor 43 | |
| Database Links |
|
| Specialist databases | |
| GPCRdb | ffar2_human (Hs), ffar2_mouse (Mm) |
| Other databases | |
| Alphafold | O15552 (Hs), Q8VCK6 (Mm), Q76EI6 (Rn) |
| ChEMBL Target | CHEMBL5493 (Hs), CHEMBL3309047 (Mm), CHEMBL3309100 (Rn) |
| Ensembl Gene | ENSG00000126262 (Hs), ENSMUSG00000051314 (Mm), ENSRNOG00000021021 (Rn) |
| Entrez Gene | 2867 (Hs), 233079 (Mm), 292794 (Rn) |
| Human Protein Atlas | ENSG00000126262 (Hs) |
| KEGG Gene | hsa:2867 (Hs), mmu:233079 (Mm), rno:292794 (Rn) |
| OMIM | 603823 (Hs) |
| Pharos | O15552 (Hs) |
| RefSeq Nucleotide | NM_005306 (Hs), NM_146187 (Mm), NM_001005877 (Rn) |
| RefSeq Protein | NP_005297 (Hs), NP_666299 (Mm), NP_001005877 (Rn) |
| UniProtKB | O15552 (Hs), Q8VCK6 (Mm), Q76EI6 (Rn) |
| Wikipedia | FFAR2 (Hs) |
| Natural/Endogenous Ligands |
| acetic acid |
| butyric acid |
| 1-methylcyclopropanecarboxylic acid |
| propanoic acid |
| trans-2-methylcrotonic acid |
Download all structure-activity data for this target as a CSV file 
| Agonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| View species-specific agonist tables | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Agonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| A series of short chain fatty acids with varying degrees of selectivity for FFA2 over FFA3 have been reported [22]. It has been noted that there are differences in the potency of short chain fatty acids at FFA2 receptors from different species [9]. For example, the bovine varient of FFA2 is activated by longer chain fatty acids, such as caproic acid (C6) and enathic acid (C7) compared to human FFA2 [7]. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Antagonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Antagonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| To date no compounds that act as antagonists at FFA2 have been reported in the peer reviewed literature but FFA2 antagonists have been described in patent applications [28]. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Allosteric Modulators | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
| Allosteric Modulator Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Further allosteric modulators based on the structure of AMG7703 have been reported [25,30] but without any significant increase in potency. | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Immunopharmacology Comments |
| FFAR2 is a GPCR activated by short-chain fatty acids, and evidence suggests that FFAR2 (and FFAR3) mediate beneficial effects associated with a fiber-rich diet. These GPCRs are of interest as targets for the treatment of inflammatory and metabolic diseases. FFAR2 is included in GtoImmuPdb as it is highly expressed on immune cells, in particular neutrophils, and evidence points to a role in diseases with dysfunctional neutrophil responses, such as inflammatory bowel disease (IBD). A Phase 2 trial of the clinical candidate GLPG0974 in ulcerative colitis has been completed (see NCT0182932). In vitro and in vivo studies suggest that the short-chain fatty acid/FFAR2 axis is modulated by metabolites of cholera toxin, that are produced by gut microbiota, which leads to enhanced mucosal antibody responses against enteric pathogen infection [31]. These discoveries help to identify FFAR2 and intestinal microbiota as critical players that underly cholera toxin's adjuvant activity, and have the potential to drive the development of more effective immunisation adjuvants. |
| Cell Type Associations | ||||||||
|
||||||||
|
| Immuno Process Associations | ||||||||||||||||||
|
||||||||||||||||||
|
||||||||||||||||||
|
||||||||||||||||||
|
||||||||||||||||||
|
| Primary Transduction Mechanisms
|
|
| Transducer | Effector/Response |
| Gq/G11 family | Phospholipase C stimulation |
| References: 2,13,18 | |
| Secondary Transduction Mechanisms |
|
| Transducer | Effector/Response |
| Gi/Go family | Adenylyl cyclase inhibition |
| References: 2,13,18 | |
| Tissue Distribution
|
||||||||
|
||||||||
|
||||||||
|
||||||||
|
||||||||
|
||||||||
|
||||||||
|
||||||||
| Tissue Distribution Comments | ||||||||
| FFA2 expression has been shown to be down-regulated in human colorectal adenocarcinomas and in human colon cancer cell lines [26]. | ||||||||
| Expression Datasets |
|
|
| Functional Assays
|
||||||||||
|
||||||||||
|
||||||||||
|
||||||||||
|
||||||||||
|
||||||||||
|
||||||||||
|
| Physiological Functions
|
||||||||
|
||||||||
|
||||||||
|
||||||||
|
||||||||
|
||||||||
|
||||||||
| Physiological Functions Comments | ||||||||
| A general function of FFA2 in nutrient sensing in the gut to maintain energy homoeostatsis has been suggested [20]. | ||||||||
| Physiological Consequences of Altering Gene Expression
|
||||||||||
|
||||||||||
|
||||||||||
|
||||||||||
|
||||||||||
| Physiological Consequences of Altering Gene Expression Comments | ||||||||||
| FFA3 is found to be upregulated in FFA2 knockout mice suggesting a compensatory mechanism may be involved with the two short chain fatty acid receptors [1]. | ||||||||||
| Phenotypes, Alleles and Disease Models
|
Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
References
1. Bjursell M, Admyre T, Göransson M, Marley AE, Smith DM, Oscarsson J, Bohlooly-Y M. (2011) Improved glucose control and reduced body fat mass in free fatty acid receptor 2-deficient mice fed a high-fat diet. Am J Physiol Endocrinol Metab, 300 (1): E211-20. [PMID:20959533]
2. Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, Muir AI, Wigglesworth MJ, Kinghorn I, Fraser NJ et al.. (2003) The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem, 278 (13): 11312-9. [PMID:12496283]
3. Brown AJ, Jupe S, Briscoe CP. (2005) A family of fatty acid binding receptors. DNA Cell Biol, 24 (1): 54-61. [PMID:15684720]
4. Dass NB, John AK, Bassil AK, Crumbley CW, Shehee WR, Maurio FP, Moore GB, Taylor CM, Sanger GJ. (2007) The relationship between the effects of short-chain fatty acids on intestinal motility in vitro and GPR43 receptor activation. Neurogastroenterol Motil, 19 (1): 66-74. [PMID:17187590]
5. Hansen AH, Sergeev E, Bolognini D, Sprenger RR, Ekberg JH, Ejsing CS, McKenzie CJ, Rexen Ulven E, Milligan G, Ulven T. (2018) Discovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic Properties. J Med Chem, 61 (21): 9534-9550. [PMID:30247908]
6. Hong YH, Nishimura Y, Hishikawa D, Tsuzuki H, Miyahara H, Gotoh C, Choi KC, Feng DD, Chen C, Lee HG et al.. (2005) Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. Endocrinology, 146 (12): 5092-9. [PMID:16123168]
7. Hudson BD, Christiansen E, Tikhonova IG, Grundmann M, Kostenis E, Adams DR, Ulven T, Milligan G. (2012) Chemically engineering ligand selectivity at the free fatty acid receptor 2 based on pharmacological variation between species orthologs. FASEB J, 26 (12): 4951-65. [PMID:22919070]
8. Hudson BD, Due-Hansen ME, Christiansen E, Hansen AM, Mackenzie AE, Murdoch H, Pandey SK, Ward RJ, Marquez R, Tikhonova IG et al.. (2013) Defining the molecular basis for the first potent and selective orthosteric agonists of the FFA2 free fatty acid receptor. J Biol Chem, 288 (24): 17296-312. [PMID:23589301]
9. Hudson BD, Tikhonova IG, Pandey SK, Ulven T, Milligan G. (2012) 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, 287 (49): 41195-209. [PMID:23066016]
10. Karaki S, Mitsui R, Hayashi H, Kato I, Sugiya H, Iwanaga T, Furness JB, Kuwahara A. (2006) Short-chain fatty acid receptor, GPR43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine. Cell Tissue Res, 324 (3): 353-60. [PMID:16453106]
11. Karaki S, Tazoe H, Hayashi H, Kashiwabara H, Tooyama K, Suzuki Y, Kuwahara A. (2008) Expression of the short-chain fatty acid receptor, GPR43, in the human colon. J Mol Histol, 39 (2): 135-42. [PMID:17899402]
12. Kebede MA, Alquier T, Latour MG, Poitout V. (2009) Lipid receptors and islet function: therapeutic implications?. Diabetes Obes Metab, 11 Suppl 4: 10-20. [PMID:19817784]
13. Le Poul E, Loison C, Struyf S, Springael JY, Lannoy V, Decobecq ME, Brezillon S, Dupriez V, Vassart G, Van Damme J et al.. (2003) Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J Biol Chem, 278 (28): 25481-9. [PMID:12711604]
14. Lee T, Schwandner R, Swaminath G, Weiszmann J, Cardozo M, Greenberg J, Jaeckel P, Ge H, Wang Y, Jiao X et al.. (2008) Identification and functional characterization of allosteric agonists for the G protein-coupled receptor FFA2. Mol Pharmacol, 74 (6): 1599-609. [PMID:18818303]
15. Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, Schilter HC, Rolph MS, Mackay F, Artis D et al.. (2009) Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature, 461 (7268): 1282-6. [PMID:19865172]
16. Nakajima T, Iikura M, Okayama Y, Matsumoto K, Uchiyama C, Shirakawa T, Yang X, Adra CN, Hirai K, Saito H. (2004) Identification of granulocyte subtype-selective receptors and ion channels by using a high-density oligonucleotide probe array. J Allergy Clin Immunol, 113 (3): 528-35. [PMID:15007357]
17. Namour F, Galien R, Van Kaem T, Van der Aa A, Vanhoutte F, Beetens J, Van't Klooster G. (2016) Safety, pharmacokinetics and pharmacodynamics of GLPG0974, a potent and selective FFA2 antagonist, in healthy male subjects. Br J Clin Pharmacol, 82 (1): 139-48. [PMID:26852904]
18. Nilsson NE, Kotarsky K, Owman C, Olde B. (2003) Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochem Biophys Res Commun, 303 (4): 1047-52. [PMID:12684041]
19. Pizzonero M, Dupont S, Babel M, Beaumont S, Bienvenu N, Blanqué R, Cherel L, Christophe T, Crescenzi B, De Lemos E et al.. (2014) Discovery and optimization of an azetidine chemical series as a free fatty acid receptor 2 (FFA2) antagonist: from hit to clinic. J Med Chem, 57 (23): 10044-57. [PMID:25380412]
20. Rasoamanana R, Darcel N, Fromentin G, Tomé D. (2012) Nutrient sensing and signalling by the gut. Proc Nutr Soc, 71 (4): 446-55. [PMID:22453062]
21. Sawzdargo M, George SR, Nguyen T, Xu S, Kolakowski LF, O'Dowd BF. (1997) 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, 239 (2): 543-7. [PMID:9344866]
22. Schmidt J, Smith NJ, Christiansen E, Tikhonova IG, Grundmann M, Hudson BD, Ward RJ, Drewke C, Milligan G, Kostenis E et al.. (2011) Selective orthosteric free fatty acid receptor 2 (FFA2) agonists: identification of the structural and chemical requirements for selective activation of FFA2 versus FFA3. J Biol Chem, 286 (12): 10628-40. [PMID:21220428]
23. Senga T, Iwamoto S, Yoshida T, Yokota T, Adachi K, Azuma E, Hamaguchi M, Iwamoto T. (2003) LSSIG is a novel murine leukocyte-specific GPCR that is induced by the activation of STAT3. Blood, 101 (3): 1185-7. [PMID:12393494]
24. Sina C, Gavrilova O, Förster M, Till A, Derer S, Hildebrand F, Raabe B, Chalaris A, Scheller J, Rehmann A et al.. (2009) G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation. J Immunol, 183 (11): 7514-22. [PMID:19917676]
25. Smith NJ, Ward RJ, Stoddart LA, Hudson BD, Kostenis E, Ulven T, Morris JC, Tränkle C, Tikhonova IG, Adams DR et al.. (2011) Extracellular loop 2 of the free fatty acid receptor 2 mediates allosterism of a phenylacetamide ago-allosteric modulator. Mol Pharmacol, 80 (1): 163-73. [PMID:21498659]
26. Tang Y, Chen Y, Jiang H, Robbins GT, Nie D. (2011) G-protein-coupled receptor for short-chain fatty acids suppresses colon cancer. Int J Cancer, 128 (4): 847-56. [PMID:20979106]
27. Tolhurst G, Heffron H, Lam YS, Parker HE, Habib AM, Diakogiannaki E, Cameron J, Grosse J, Reimann F, Gribble FM. (2012) Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes, 61 (2): 364-71. [PMID:22190648]
28. Ulven T. (2012) Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets. Front Endocrinol (Lausanne), 3: 111. [PMID:23060857]
29. Vinolo MA, Ferguson GJ, Kulkarni S, Damoulakis G, Anderson K, Bohlooly-Y M, Stephens L, Hawkins PT, Curi R. (2011) SCFAs induce mouse neutrophil chemotaxis through the GPR43 receptor. PLoS ONE, 6 (6): e21205. [PMID:21698257]
30. Wang Y, Jiao X, Kayser F, Liu J, Wang Z, Wanska M, Greenberg J, Weiszmann J, Ge H, Tian H et al.. (2010) The first synthetic agonists of FFA2: Discovery and SAR of phenylacetamides as allosteric modulators. Bioorg Med Chem Lett, 20 (2): 493-8. [PMID:20005104]
31. Yang W, Xiao Y, Huang X, Chen F, Sun M, Bilotta AJ, Xu L, Lu Y, Yao S, Zhao Q et al.. (2019) Microbiota Metabolite Short-Chain Fatty Acids Facilitate Mucosal Adjuvant Activity of Cholera Toxin through GPR43. J Immunol, 203 (1): 282-292. [PMID:31076530]
32. Zaibi MS, Stocker CJ, O'Dowd J, Davies A, Bellahcene M, Cawthorne MA, Brown AJ, Smith DM, Arch JR. (2010) Roles of GPR41 and GPR43 in leptin secretory responses of murine adipocytes to short chain fatty acids. FEBS Lett, 584 (11): 2381-6. [PMID:20399779]
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License