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FFA1 receptor

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 225

Nomenclature: FFA1 receptor

Family: Free fatty acid receptors

Gene and Protein Information Click here for help
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 300 19q13.12 FFAR1 free fatty acid receptor 1 21
Mouse 7 300 7 B1 Ffar1 free fatty acid receptor 1 2
Rat 7 300 1q21 Ffar1 free fatty acid receptor 1 2
Previous and Unofficial Names Click here for help
GPR40 [21] | FFA1R | G protein-coupled receptor 40
Database Links Click here for help
Specialist databases
GPCRDB ffar1_human (Hs), ffar1_mouse (Mm), ffar1_rat (Rn)
Other databases
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of Human GPR40 bound to allosteric agonist TAK-875
PDB Id:  4PHU
Ligand:  fasiglifam
Resolution:  2.33Å
Species:  Human
References:  23
Natural/Endogenous Ligands Click here for help
docosahexaenoic acid
α-linolenic acid
myristic acid
oleic acid
long chain carboxylic acids

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Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 4 [PMID: 27074625] Small molecule or natural product Primary target of this compound Hs Agonist 8.1 – 8.4 pKd 6
pKd 8.1 – 8.4 (Kd 7.4x10-9 – 4x10-9 M) [6]
AMG-837 Small molecule or natural product Hs Agonist 8.5 pEC50 16
pEC50 8.5 [16]
TUG-770 Small molecule or natural product Hs Full agonist 8.2 pEC50 5
pEC50 8.2 [5]
TUG-905 Small molecule or natural product Primary target of this compound Hs Agonist 8.1 pEC50 4
pEC50 8.1 (EC50 9x10-9 M) [4]
HWL-088 Small molecule or natural product Hs Agonist 7.7 pEC50 3
pEC50 7.7 (EC50 1.89x10-8 M) [3]
TUG-424 Small molecule or natural product Hs Full agonist 7.5 pEC50 7
pEC50 7.5 [7]
GW9508 Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 7.3 pEC50 1
pEC50 7.3 [1]
fasiglifam Small molecule or natural product Ligand has a PDB structure Hs Agonist 7.1 pEC50 14,19,23,29
pEC50 7.1 [14,19,23,29]
compound B [PMID:18477808] Small molecule or natural product Hs Full agonist 6.1 pEC50 27
pEC50 6.1 [27]
medica 16 Small molecule or natural product Hs Full agonist 5.9 pEC50 15
pEC50 5.9 [15]
docosahexaenoic acid Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Full agonist 5.4 – 6.0 pEC50 2,13
pEC50 5.4 – 6.0 [2,13]
rosiglitazone Small molecule or natural product Approved drug Click here for species-specific activity table Hs Full agonist 5.6 pEC50 15
pEC50 5.6 [15]
α-linolenic acid Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Full agonist 4.6 – 5.7 pEC50 2,13,15
pEC50 4.6 – 5.7 [2,13,15]
linoleic acid Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist 4.4 – 5.7 pEC50 2,13,15
pEC50 4.4 – 5.7 (EC50 3.98x10-5 – 1.99x10-6 M) [2,13,15]
oleic acid Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Full agonist 3.9 – 5.7 pEC50 2,13,15
pEC50 3.9 – 5.7 [2,13,15]
myristic acid Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Full agonist 4.5 – 5.1 pEC50 2,13,15
pEC50 4.5 – 5.1 [2,13,15]
palmitic acid Small molecule or natural product Ligand has a PDB structure Hs Full agonist 3.8 – 5.3 pEC50 2,13,15
pEC50 3.8 – 5.3 [2,13,15]
setogepram Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Agonist 3.0 pEC50 10
pEC50 3.0 (EC50 1.047x10-3 M) [10]
Description: In a β-arrestin 2 recruitment assay measured by BRET.
Agonist Comments
Other small-molecule agonists have been described in [11,18,22].

For information on the key residues involved in ligand binding see references [26,28].

PBI-4050 couples the receptor to Gαq, Gαi and Gα13, but not Gαs [10].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
GW1100 Small molecule or natural product Hs Antagonist 6.0 pIC50 1,25
pIC50 6.0 (IC50 1x10-6 M) [1,25]
Allosteric Modulator Comments
FFA1 allosteric binding sites are reported in [16].
Immunopharmacology Comments
Studies in Ffar1 (Gpr40) knockout mice indicate that it plays a protective role in fibrotic kidney disease models [10].
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gq/G11 family Adenylyl cyclase inhibition
Phospholipase C stimulation
References:  2,13,15
Secondary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gs family
Gi/Go family
Adenylyl cyclase stimulation
Phospholipase C stimulation
Phospholipase A2 stimulation
Comments:  Stimulation of cAMP signalling in MIN6 insulinoma cells may enhance insulin release. Signalling through the Gαi pathway may play a role in proliferation of human breast cancer cell-lines.
References:  8,12
Tissue Distribution Click here for help
Pancreatic islets, GI tract, brain, monocytes.
Species:  Human
Technique:  RT-PCR.
References:  2
Islet α-cells.
Species:  Mouse
Technique:  immunocytochemistry.
References:  8
Islets.
Species:  Mouse
Technique:  in situ hybridisation.
References:  24
Pancreatic islets, GI tract.
Species:  Rat
Technique:  RT-PCR.
References:  13
Islets.
Species:  Rat
Technique:  in situ hybridisation.
References:  2,13
Expression Datasets Click here for help

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays Click here for help
Measurement of glucose-stimulated insulin secretion in MIN6 cells endogenously expressing the FFA1 receptor.
Species:  Mouse
Tissue:  MIN6
Response measured:  Stimulation of insulin secretion.
References:  1
Measurement of Ca2+ levels in HEK 293 cells transfected with the human FFA1 receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Increase in intracellular Ca2+ concentration.
References:  2
Glucagon release from mouse islets endogenously expressing the FFA1 receptor.
Species:  Mouse
Tissue:  Pancreatic islets.
Response measured:  Increase in glucagon secretion.
References:  9
[35S]GTPγS binding in HEK 293 cells expressing GPR40-Gαq fusion protein.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Increase in [35S]GTPγS binding.
References:  25
Stimulation of FUS3 reporter gene in HFF11 cell-lines expressing the FFA1 receptor and aequorin.
Species:  Human
Tissue:  Cervical cancer cell-line.
Response measured:  Stimulation of Ca2+-mediated luminescence.
References:  15
Physiological Functions Click here for help
Islet insulin secretion (role in fatty-acid mediated potentiation).
Species:  Mouse
Tissue:  Pancreatic islets.
References:  24
Increase in glucagon secretion.
Species:  Mouse
Tissue:  Pancreatic islets.
References:  9,20
Physiological Consequences of Altering Gene Expression Click here for help
FFA1 receptor knockout mice exhibit reduced insulin secretion in response to fatty acids. They are protected from obesity-induced hyperinsulinemia, hepatic steatosis, hypertriglyceridemia, increase hepatic glucose output, hyperglycemia and glucose intolerance.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  24
Overexpression of the FFA1 receptor in pancreatic β-cells under PDX-1 promotor. Mice are glucose intolerant and exhibit much reduced insulin secretion. Mice become diabetic shortly after birth.
Species:  Human
Tissue: 
Technique:  Transgenesis.
References:  24
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Ffar1tm1Dgen Ffar1tm1Dgen/Ffar1tm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:2684079  MP:0005418 abnormal circulating hormone level PMID: 18678612 
Ffar1tm1Dgen Ffar1tm1Dgen/Ffar1tm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:2684079  MP:0001560 abnormal circulating insulin level PMID: 18678612 
Ffar1tm1Heed Ffar1tm1Heed/Ffar1tm1Heed
Not Specified
MGI:2684079  MP:0003383 abnormal gluconeogenesis PMID: 16054069 
Ffar1tm1Dgen Ffar1tm1Dgen/Ffar1tm1Dgen
involves: 129P2/OlaHsd * C57BL/6N
MGI:2684079  MP:0001985 abnormal gustatory system physiology PMID: 20573884 
Ffar1tm1Dgen Ffar1tm1Dgen/Ffar1tm1Dgen
involves: 129P2/OlaHsd * C57BL/6N
MGI:2684079  MP:0010055 abnormal sensory neuron physiology PMID: 20573884 
Ffar1tm1Dgen Ffar1tm1Dgen/Ffar1tm1Dgen
involves: 129P2/OlaHsd * C57BL/6N
MGI:2684079  MP:0001986 abnormal taste sensitivity PMID: 20573884 
Ffar1tm1Heed Ffar1tm1Heed/Ffar1tm1Heed
Not Specified
MGI:2684079  MP:0000187 abnormal triglyceride level PMID: 16054069 
Ffar1tm1Dgen Ffar1tm1Dgen/Ffar1tm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:2684079  MP:0000187 abnormal triglyceride level PMID: 18678612 
Ffar1tm1Dgen Ffar1tm1Dgen/Ffar1tm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:2684079  MP:0002696 decreased circulating glucagon level PMID: 18678612 
Ffar1tm1Heed Ffar1tm1Heed/Ffar1tm1Heed
Not Specified
MGI:2684079  MP:0002727 decreased circulating insulin level PMID: 16054069 
Ffar1tm1Dgen Ffar1tm1Dgen/Ffar1tm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:2684079  MP:0002644 decreased circulating triglyceride level PMID: 18678612 
Ffar1tm1Lex Ffar1tm1Lex/Ffar1tm1Lex
involves: 129 * C57BL/6
MGI:2684079  MP:0003059 decreased insulin secretion PMID: 17395749 
Ffar1tm1Heed Ffar1tm1Heed/Ffar1tm1Heed
Not Specified
MGI:2684079  MP:0003059 decreased insulin secretion PMID: 16054069 
Ffar1tm1Heed Ffar1tm1Heed/Ffar1tm1Heed
Not Specified
MGI:2684079  MP:0005292 improved glucose tolerance PMID: 16054069 
Ffar1tm1Dgen Ffar1tm1Dgen/Ffar1tm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:2684079  MP:0003909 increased eating behavior PMID: 18678612 
Ffar1tm1Heed Ffar1tm1Heed/Ffar1tm1Heed
Not Specified
MGI:2684079  MP:0002891 increased insulin sensitivity PMID: 16054069 
Ffar1tm1Dgen Ffar1tm1Dgen/Ffar1tm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:2684079  MP:0009355 increased liver triglyceride level PMID: 18678612 
Ffar1tm1Heed Ffar1tm1Heed/Ffar1tm1Heed
Not Specified
MGI:2684079  MP:0002310 increased resistance to hepatic steatosis PMID: 16054069 
Biologically Significant Variants Click here for help
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  R211H
References:  20
General Comments
Expression of the FFA1 receptor has been found by immunocytochemistry in the monkey brain [17].

References

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1. Briscoe CP, Peat AJ, McKeown SC, Corbett DF, Goetz AS, Littleton TR, McCoy DC, Kenakin TP, Andrews JL, Ammala C et al.. (2006) Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules. Br J Pharmacol, 148 (5): 619-28. [PMID:16702987]

2. Briscoe CP, Tadayyon M, Andrews JL, Benson WG, Chambers JK, Eilert MM, Ellis C, Elshourbagy NA, Goetz AS, Minnick DT et al.. (2003) The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem, 278 (13): 11303-11. [PMID:12496284]

3. Chen Y, Ren Q, Zhou Z, Deng L, Hu L, Zhang L, Li Z. (2020) HWL-088, a new potent free fatty acid receptor 1 (FFAR1) agonist, improves glucolipid metabolism and acts additively with metformin in ob/ob diabetic mice. Br J Pharmacol, 177 (10): 2286-2302. [PMID:31971610]

4. Christiansen E, Due-Hansen ME, Urban C, Grundmann M, Schröder R, Hudson BD, Milligan G, Cawthorne MA, Kostenis E, Kassack MU et al.. (2012) Free fatty acid receptor 1 (FFA1/GPR40) agonists: mesylpropoxy appendage lowers lipophilicity and improves ADME properties. J Med Chem, 55 (14): 6624-8. [PMID:22724451]

5. Christiansen E, Hansen SV, Urban C, Hudson BD, Wargent ET, Grundmann M, Jenkins L, Zaibi M, Stocker CJ, Ullrich S et al.. (2013) Discovery of TUG-770: A Highly Potent Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonist for Treatment of Type 2 Diabetes. ACS Med Chem Lett, 4 (5): 441-445. [PMID:23687558]

6. Christiansen E, Hudson BD, Hansen AH, Milligan G, Ulven T. (2016) Development and Characterization of a Potent Free Fatty Acid Receptor 1 (FFA1) Fluorescent Tracer. J Med Chem, 59 (10): 4849-58. [PMID:27074625]

7. Christiansen E, Urban C, Merten N, Liebscher K, Karlsen KK, Hamacher A, Spinrath A, Bond AD, Drewke C, Ullrich S et al.. (2008) Discovery of potent and selective agonists for the free fatty acid receptor 1 (FFA(1)/GPR40), a potential target for the treatment of type II diabetes. J Med Chem, 51 (22): 7061-4. [PMID:18947221]

8. Feng DD, Luo Z, Roh SG, Hernandez M, Tawadros N, Keating DJ, Chen C. (2006) Reduction in voltage-gated K+ currents in primary cultured rat pancreatic beta-cells by linoleic acids. Endocrinology, 147: 674-682. [PMID:16254037]

9. Flodgren E, Olde B, Meidute-Abaraviciene S, Winzell MS, Ahrén B, Salehi A. (2007) GPR40 is expressed in glucagon producing cells and affects glucagon secretion. Biochem Biophys Res Commun, 354 (1): 240-5. [PMID:17214971]

10. Gagnon L, Leduc M, Thibodeau JF, Zhang MZ, Grouix B, Sarra-Bournet F, Gagnon W, Hince K, Tremblay M, Geerts L et al.. (2018) A Newly Discovered Antifibrotic Pathway Regulated by Two Fatty Acid Receptors: GPR40 and GPR84. Am J Pathol, 188 (5): 1132-1148. [PMID:29454750]

11. Garrido DM, Corbett DF, Dwornik KA, Goetz AS, Littleton TR, McKeown SC, Mills WY, Smalley Jr TL, Briscoe CP, Peat AJ. (2006) Synthesis and activity of small molecule GPR40 agonists. Bioorg Med Chem Lett, 16 (7): 1840-5. [PMID:16439116]

12. Hardy S, St-Onge GG, Joly E, Langelier Y, Prentki M. (2005) Oleate promotes the proliferation of breast cancer cells via the G protein-coupled receptor GPR40. J Biol Chem, 280 (14): 13285-91. [PMID:15695516]

13. Itoh Y, Kawamata Y, Harada M, Kobayashi M, Fujii R, Fukusumi S, Ogi K, Hosoya M, Tanaka Y, Uejima H et al.. (2003) Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature, 422 (6928): 173-6. [PMID:12629551]

14. Kaku K, Enya K, Nakaya R, Ohira T, Matsuno R. (2015) Efficacy and safety of fasiglifam (TAK-875), a G protein-coupled receptor 40 agonist, in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise: a randomized, double-blind, placebo-controlled, phase III trial. Diabetes Obes Metab, 17 (7): 675-81. [PMID:25787200]

15. Kotarsky K, Nilsson NE, Flodgren E, Owman C, Olde B. (2003) A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs. Biochem Biophys Res Commun, 301 (2): 406-10. [PMID:12565875]

16. Lin DC, Guo Q, Luo J, Zhang J, Nguyen K, Chen M, Tran T, Dransfield PJ, Brown SP, Houze J et al.. (2012) Identification and pharmacological characterization of multiple allosteric binding sites on the free fatty acid 1 receptor. Mol Pharmacol, 82 (5): 843-59. [PMID:22859723]

17. Ma D, Tao B, Warashina S, Kotani S, Lu L, Kaplamadzhiev DB, Mori Y, Tonchev AB, Yamashima T. (2007) Expression of free fatty acid receptor GPR40 in the central nervous system of adult monkeys. Neurosci Res, 58 (4): 394-401. [PMID:17583366]

18. McKeown SC, Corbett DF, Goetz AS, Littleton TR, Bigham E, Briscoe CP, Peat AJ, Watson SP, Hickey DM. (2007) Solid phase synthesis and SAR of small molecule agonists for the GPR40 receptor. Bioorg Med Chem Lett, 17 (6): 1584-9. [PMID:17240142]

19. Negoro N, Sasaki S, Mikami S, Ito M, Suzuki M, Tsujihata Y, Ito R, Harada A, Takeuchi K, Suzuki N et al.. (2010) Discovery of TAK-875: A Potent, Selective, and Orally Bioavailable GPR40 Agonist. ACS Med Chem Lett, 1 (6): 290-4. [PMID:24900210]

20. Ogawa T, Hirose H, Miyashita K, Saito I, Saruta T. (2005) GPR40 gene Arg211His polymorphism may contribute to the variation of insulin secretory capacity in Japanese men. Metab Clin Exp, 54 (3): 296-9. [PMID:15736105]

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. Song F, Lu S, Gunnet J, Xu JZ, Wines P, Proost J, Liang Y, Baumann C, Lenhard J, Murray WV et al.. (2007) Synthesis and biological evaluation of 3-aryl-3-(4-phenoxy)-propionic acid as a novel series of G protein-coupled receptor 40 agonists. J Med Chem, 50 (12): 2807-17. [PMID:17500511]

23. Srivastava A, Yano J, Hirozane Y, Kefala G, Gruswitz F, Snell G, Lane W, Ivetac A, Aertgeerts K, Nguyen J et al.. (2014) High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. Nature, 513 (7516): 124-7. [PMID:25043059]

24. Steneberg P, Rubins N, Bartoov-Shifman R, Walker MD, Edlund H. (2005) The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse. Cell Metab, 1 (4): 245-58. [PMID:16054069]

25. Stoddart LA, Brown AJ, Milligan G. (2007) Uncovering the pharmacology of the G protein-coupled receptor GPR40: high apparent constitutive activity in guanosine 5'-O-(3-[35S]thio)triphosphate binding studies reflects binding of an endogenous agonist. Mol Pharmacol, 71 (4): 994-1005. [PMID:17200419]

26. Sum CS, Tikhonova IG, Neumann S, Engel S, Raaka BM, Costanzi S, Gershengorn MC. (2007) Identification of residues important for agonist recognition and activation in GPR40. J Biol Chem, 282 (40): 29248-55. [PMID:17699519]

27. Tan CP, Feng Y, Zhou YP, Eiermann GJ, Petrov A, Zhou C, Lin S, Salituro G, Meinke P, Mosley R et al.. (2008) Selective small-molecule agonists of G protein-coupled receptor 40 promote glucose-dependent insulin secretion and reduce blood glucose in mice. Diabetes, 57 (8): 2211-9. [PMID:18477808]

28. Tikhonova IG, Sum CS, Neumann S, Thomas CJ, Raaka BM, Costanzi S, Gershengorn MC. (2007) Bidirectional, iterative approach to the structural delineation of the functional "chemoprint" in GPR40 for agonist recognition. J Med Chem, 50 (13): 2981-9. [PMID:17552505]

29. Tsujihata Y, Ito R, Suzuki M, Harada A, Negoro N, Yasuma T, Momose Y, Takeuchi K. (2011) TAK-875, an orally available G protein-coupled receptor 40/free fatty acid receptor 1 agonist, enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia in type 2 diabetic rats. J Pharmacol Exp Ther, 339 (1): 228-37. [PMID:21752941]

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