GPBA receptor | Bile acid receptor | IUPHAR/BPS Guide to PHARMACOLOGY

GPBA receptor

Target id: 37

Nomenclature: GPBA receptor

Family: Bile acid receptor

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

   GtoImmuPdb view: OFF :     GPBA receptor has curated GtoImmuPdb data

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 330 2q35 GPBAR1 G protein-coupled bile acid receptor 1 10
Mouse 7 329 1 C4 Gpbar1 G protein-coupled bile acid receptor 1
Rat 7 329 9q33 Gpbar1 G protein-coupled bile acid receptor 1
Previous and Unofficial Names
BG37 [10] | hGPCR19 [14] | M-BAR [10] | TGR5 [1,8,16] | GPCR19 | GPR131 | GPBAR1 | G protein-coupled bile acid receptor 1 | membrane-type receptor for bile acids
Database Links
Specialist databases
GPCRDB gpbar_human (Hs), gpbar_mouse (Mm), gpbar_rat (Rn)
Other databases
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
chenodeoxycholic acid
cholic acid
deoxycholic acid
lithocholic acid
Potency order of endogenous ligands
lithocholic acid > deoxycholic acid > chenodeoxycholic acid, cholic acid  [8,10]

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
Ligand Sp. Action Affinity Units Reference
compound 15 [PMID: 25411721] Hs Agonist 9.4 pEC50 6
pEC50 9.4 [6]
Description: Assessed in a cAMP production assay in Jurkat cells expressing exogenous hGPBAR1.
compound 15 [PMID: 25411721] Mm Agonist 7.5 pEC50 6
pEC50 7.5 [6]
Description: Assessed in a cAMP production assay in Jurkat cells expressing exogenous mGPBAR1.
lithocholic acid Hs Full agonist 7.5 pEC50 10
pEC50 7.5 [10]
deoxycholic acid Hs Full agonist 6.2 pEC50 10
pEC50 6.2 [10]
S-EMCA Mm Agonist 6.1 pEC50 11
pEC50 6.1 [11]
betulinic acid Hs Full agonist 6.0 pEC50 3
pEC50 6.0 (EC50 1.04x10-6 M) [3]
oleanolic acid Hs Full agonist 5.7 pEC50 13
pEC50 5.7 (EC50 2.25x10-6 M) [13]
chenodeoxycholic acid Hs Full agonist 5.4 pEC50 10
pEC50 5.4 [10]
cholic acid Hs Full agonist 5.0 pEC50 10
pEC50 5.0 [10]
View species-specific agonist tables
Agonist Comments
pEC50 values were determined by measuring intracellular cAMP levels in HEK 293 cells transfected with human GPBA in response to ligand binding [10].
Benzyl 2-keto-6-methyl-4-(2-thienyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate has also been shown to be a highly selective synthetic GPBA agonist [16].
Immunopharmacology Comments
The GPBA receptor (GPBAR) was historically identified as a metabolic regulator with roles in energy homeostasis, bile acid homeostasis, and glucose metabolism. More recently additional functions for the GPBA receptor such as regulation of the inflammatory response, cancer and liver regeneration have been described [4]. GPBAR agonists reduce the production of proinflammatory cytokines and stabilize the alternative macrophage phenotype [6]. This action appears to be mediated by regulation of the NLRP3 inflammasome pathway. The GPBAR agonist S-EMCA (INT-777) produces a protective (anti-inflammatory) effect in many inflammatory diseases in vivo [2,5,12,15], and has recently been shown to attenuate the severity of acute pancreatitis in a mouse model (an effect associated with reduced reactive oxygen species (ROS) production and a reduction in the activation of the NLRP3 inflammasome) [9].
Primary Transduction Mechanisms
Transducer Effector/Response
Gs family Adenylate cyclase stimulation
References:  8
Tissue Distribution
Placenta, spleen > lung, liver, kidney, adrenal gland, stomach, small intestine, adipose, uterus, mammary gland, bone marrow, lymph node, fetal kidney.
Leukocytes: CD14+ > mononuclear cells.
Species:  Human
Technique:  RT-PCR
References:  8
Heart, skeletal muscle, spleen, kidney, liver, small intestine, placenta, leukocytes, stomach, duodenum, ileocecum, ileum, jejunum, ascending colon, transverse colon, descending colon, cecum, liver and enteroendocrine cells.
Species:  Human
Technique:  Northern blot.
References:  10
Skeletal muscle myoblasts > spleen > lung > kidney > liver > heart > brain.
Species:  Human
Technique:  RT-PCR.
References:  16
Expression Datasets

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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
Measurement of cAMP levels in HEK 293 cells transfected with the human GPBA receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Intracellular cAMP accumulation.
References:  10
Measurement of cAMP levels in CHO cells transfected with the human GPBA receptor, using a luciferase reporter gene.
Species:  Human
Tissue:  CHO cells.
Response measured:  Intracellular cAMP accumulation.
References:  8,16
Measurement of GLP-1 secretion from murine STC-1 cells endogenously expressing the GPBA receptor in the presence of an adenylate cyclase inhibitor/activator or cAMP elevator.
Species:  Mouse
Tissue:  STC-1 cell line.
Response measured:  GLP-1 secretion via cAMP production.
References:  7
Measurement of type 2 iodothyronine deiodinase (DIO2) expression in BAT cells endogenously expressing the GPBA receptor.
Species:  Mouse
Tissue:  BAT cells.
Response measured:  Induction of DIO2 expression.
References:  16
Measurement of type 2 iodothyronine deiodinase (DIO2) activity, oxygen consumption and extracellular acidification rate in skeletal muscle myoblasts endogenously expressing the GPBA receptor.
Species:  Human
Tissue:  Skeletal muscle myoblasts.
Response measured:  Induction of DIO2 activity and subsequent increase in oxygen consumption and extracellular acidification rate.
References:  16
Physiological Functions
GLP-1 secretion.
Species:  Mouse
Tissue:  STC-1 cells in vitro.
References:  7
Increase in energy expenditure.
Species:  Mouse
Tissue:  In vivo (brown adipose tissue).
References:  16
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Gpbar1tm1Ktan Gpbar1tm1Ktan/Gpbar1tm1Ktan
involves: 129X1/SvJ * C57BL/6N
MGI:2653863  MP:0005452 abnormal adipose tissue amount PMID: 17065403 
Gpbar1+|Gpbar1tm1Ktan Gpbar1tm1Ktan/Gpbar1+
involves: 129X1/SvJ * C57BL/6N
MGI:2653863  MP:0005452 abnormal adipose tissue amount PMID: 17065403 
Gpbar1tm1Gvas Gpbar1tm1Gvas/Gpbar1tm1Gvas
involves: 129S1/SvImJ * C57BL/6
MGI:2653863  MP:0004773 abnormal bile composition PMID: 16724960 
Gpbar1tm1Gvas Gpbar1tm1Gvas/Gpbar1tm1Gvas
involves: 129S1/SvImJ * C57BL/6
MGI:2653863  MP:0002929 abnormal bile duct development PMID: 16724960 
Gpbar1tm1Ktan Gpbar1tm1Ktan/Gpbar1tm1Ktan
involves: 129X1/SvJ * C57BL/6N
MGI:2653863  MP:0005365 abnormal bile salt homeostasis PMID: 17065403 
Gpbar1tm1Gvas Gpbar1tm1Gvas/Gpbar1tm1Gvas
involves: 129S1/SvImJ * C57BL/6
MGI:2653863  MP:0005278 abnormal cholesterol homeostasis PMID: 16724960 
Gpbar1tm1Gvas Gpbar1tm1Gvas/Gpbar1tm1Gvas
involves: 129S1/SvImJ * C57BL/6
MGI:2653863  MP:0005084 abnormal gallbladder morphology PMID: 16724960 
Gpbar1tm1.2Auw Gpbar1tm1.2Auw/Gpbar1tm1.2Auw
involves: 129/Sv * C57BL/6J
MGI:2653863  MP:0008874 decreased physiological sensitivity to xenobiotic PMID: 19723493 
Gpbar1tm1Gvas Gpbar1tm1Gvas/Gpbar1tm1Gvas
involves: 129S1/SvImJ * C57BL/6
MGI:2653863  MP:0002830 gallstones PMID: 16724960 
Gpbar1tm1.2Auw Gpbar1tm1.2Auw/Gpbar1tm1.2Auw
involves: 129/Sv * C57BL/6J
MGI:2653863  MP:0005293 impaired glucose tolerance PMID: 19723493 
Gpbar1tm1Ktan Gpbar1tm1Ktan/Gpbar1tm1Ktan
involves: 129X1/SvJ * C57BL/6N
MGI:2653863  MP:0005178 increased circulating cholesterol level PMID: 17065403 
Gpbar1tm1.2Auw Gpbar1tm1.2Auw/Gpbar1tm1.2Auw
involves: 129/Sv * C57BL/6J
MGI:2653863  MP:0002079 increased circulating insulin level PMID: 19723493 
Gpbar1tm1Ktan Gpbar1tm1Ktan/Gpbar1tm1Ktan
involves: 129X1/SvJ * C57BL/6N
MGI:2653863  MP:0005455 increased susceptibility to weight gain PMID: 17065403 
Gpbar1+|Gpbar1tm1Ktan Gpbar1tm1Ktan/Gpbar1+
involves: 129X1/SvJ * C57BL/6N
MGI:2653863  MP:0005455 increased susceptibility to weight gain PMID: 17065403 
General Comments
For an overview of bile acids and their role in energy homeostasis see reference [1].

References

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1. Baxter JD, Webb P. (2006) Metabolism: bile acids heat things up. Nature, 439: 402-403. [PMID:16437098]

2. de Oliveira MC, Gilglioni EH, de Boer BA, Runge JH, de Waart DR, Salgueiro CL, Ishii-Iwamoto EL, Oude Elferink RP, Gaemers IC. (2016) Bile acid receptor agonists INT747 and INT777 decrease oestrogen deficiency-related postmenopausal obesity and hepatic steatosis in mice. Biochim. Biophys. Acta, 1862 (11): 2054-2062. [PMID:27475255]

3. Genet C, Strehle A, Schmidt C, Boudjelal G, Lobstein A, Schoonjans K, Souchet M, Auwerx J, Saladin R, Wagner A. (2010) Structure-activity relationship study of betulinic acid, a novel and selective TGR5 agonist, and its synthetic derivatives: potential impact in diabetes. J. Med. Chem., 53 (1): 178-90. [PMID:19911773]

4. Guo C, Chen WD, Wang YD. (2016) TGR5, Not Only a Metabolic Regulator. Front Physiol, 7: 646. [PMID:28082913]

5. Guo C, Xie S, Chi Z, Zhang J, Liu Y, Zhang L, Zheng M, Zhang X, Xia D, Ke Y et al.. (2016) Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome. Immunity, 45 (4): 802-816. [PMID:27692610]

6. Högenauer K, Arista L, Schmiedeberg N, Werner G, Jaksche H, Bouhelal R, Nguyen DG, Bhat BG, Raad L, Rauld C et al.. (2014) G-protein-coupled bile acid receptor 1 (GPBAR1, TGR5) agonists reduce the production of proinflammatory cytokines and stabilize the alternative macrophage phenotype. J. Med. Chem., 57 (24): 10343-54. [PMID:25411721]

7. Katsuma S, Hirasawa A, Tsujimoto G. (2005) Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochem Biophys Res Commun, 329: 386-390. [PMID:15721318]

8. Kawamata Y, Fujii R, Hosoya M, Harada M, Yoshida H, Miwa M, Fukusumi S, Habata Y, Itoh T, Shintani Y, Hinuma S, Fujisawa Y, Fujino M. (2003) A G protein-coupled receptor responsive to bile acids. J Biol Chem., 278: 9435-9440. [PMID:12524422]

9. Li B, Yang N, Li C, Li C, Gao K, Xie X, Dong X, Yang J, Yang Q, Tong Z et al.. (2018) INT-777, a bile acid receptor agonist, extenuates pancreatic acinar cells necrosis in a mouse model of acute pancreatitis. Biochem. Biophys. Res. Commun., 503 (1): 38-44. [PMID:29859191]

10. Maruyama T, Miyamoto Y, Nakamura T, Tamai Y, Okada H, Sugiyama E, Nakamura T, Itadani H, Tanaka K. (2002) Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun., 298: 714-719. [PMID:12419312]

11. Pellicciari R, Gioiello A, Macchiarulo A, Thomas C, Rosatelli E, Natalini B, Sardella R, Pruzanski M, Roda A, Pastorini E et al.. (2009) Discovery of 6alpha-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a potent and selective agonist for the TGR5 receptor, a novel target for diabesity. J. Med. Chem., 52 (24): 7958-61. [PMID:20014870]

12. Pols TW, Nomura M, Harach T, Lo Sasso G, Oosterveer MH, Thomas C, Rizzo G, Gioiello A, Adorini L, Pellicciari R et al.. (2011) TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab., 14 (6): 747-57. [PMID:22152303]

13. Sato H, Genet C, Strehle A, Thomas C, Lobstein A, Wagner A, Mioskowski C, Auwerx J, Saladin R. (2007) Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea europaea. Biochem. Biophys. Res. Commun., 362 (4): 793-8. [PMID:17825251]

14. Takeda S, Kadowaki S, Haga T, Takaesu H, Mitaku S. (2002) Identification of G protein-coupled receptor genes from the human genome sequence. FEBS Lett, 520: 97-101. [PMID:12044878]

15. Wang XX, Edelstein MH, Gafter U, Qiu L, Luo Y, Dobrinskikh E, Lucia S, Adorini L, D'Agati VD, Levi J et al.. (2016) G Protein-Coupled Bile Acid Receptor TGR5 Activation Inhibits Kidney Disease in Obesity and Diabetes. J. Am. Soc. Nephrol., 27 (5): 1362-78. [PMID:26424786]

16. Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, Messaddeq N, Harney JW, Ezaki O, Kodama T, Schoonjans K, Bianco AC, Auwerx J. (2006) Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature, 439: 484-489. [PMID:16400329]

Contributors

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How to cite this page

Tom I. Bonner, Anthony P. Davenport, Rebecca Hills, Edward Rosser.
Bile acid receptor: GPBA receptor. Last modified on 22/06/2018. Accessed on 14/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=37.