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GPBAR1
Identifiers
Aliases	GPBAR1, BG37, GPCR19, GPR131, M-BAR, TGR5, G protein-coupled bile acid receptor, G protein-coupled bile acid receptor 1
External IDs	OMIM: 610147; MGI: 2653863; HomoloGene: 18125; GeneCards: GPBAR1; OMA:GPBAR1 - orthologs
Gene location (Human) Chr. Chromosome 2 (human) Band 2q35 Start 218,259,496 bp End 218,263,861 bp
Gene location (Mouse) Chr. Chromosome 1 (mouse) Band 1 C3|1 38.53 cM Start 74,317,709 bp End 74,318,783 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in testicle monocyte granulocyte decidua gallbladder blood subcutaneous adipose tissue apex of heart spleen gastric mucosa Top expressed in blastocyst embryo embryo yolk sac urinary bladder placenta intestine ileum zygote duodenum More reference expression data BioGPS More reference expression data
Gene ontology Molecular function bile acid receptor activity G protein-coupled receptor activity G protein-coupled bile acid receptor activity signal transducer activity Cellular component cytoplasm integral component of membrane plasma membrane membrane Biological process signal transduction cell surface bile acid receptor signaling pathway regulation of bicellular tight junction assembly G protein-coupled receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 151306 227289 Ensembl ENSG00000179921 ENSMUSG00000064272 UniProt Q8TDU6 Q80SS6 RefSeq (mRNA) NM_001077191 NM_001077194 NM_170699 NM_001321950 NM_174985 RefSeq (protein) NP_001070659 NP_001070662 NP_001308879 NP_733800 NP_778150 Location (UCSC) Chr 2: 218.26 – 218.26 Mb Chr 1: 74.32 – 74.32 Mb PubMed search
Wikidata
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The G protein-coupled bile acid receptor 1 (GPBAR1) also known as G-protein coupled receptor 19 (GPCR19), membrane-type receptor for bile acids (M-BAR) or Takeda G protein-coupled receptor 5 (TGR5) is a protein that in humans is encoded by the GPBAR1 gene. Activated by bile acids, these receptors play a crucial role in metabolic regulation, including insulin secretion and energy balance, and are found in the gastrointestinal tract as well as other tissues throughout the body.

History

TGR5 receptors were first discovered by Takaharu Maruyama in 2002. It was the first membrane bound G protein coupled receptor that was discovered for faster bile acid signaling. Initially, up until the late 90's, bile acids were known only for its metabolic function of emulsifying fats and keeping cholesterol homeostasis. It wasn't until 1999 when researchers began exploring into its role as a hormone and signaling molecule with the discovery of the nuclear bile acid receptors, Farnesoid X Receptors (FXR).

Location

TGR5 receptors are primarily located in gastrointestinal tracts where bile acid functions are most prevalent. They can also be found throughout the body, including the nervous system, immune system, and various muscle groups, aiding in the tasks that are relevant to their respective locations.

Function

The primary function of the TGR5 receptor is for the binding of bile acid to elicit second messenger systems in the metabolic role of bile acids. It is also a receptor for other agonists, including activating various other pathways responsible for responses like inflammation.

TGR5 receptors are a member of the G protein-coupled receptor (GPCR) superfamily. As mentioned, this protein functions as a cell surface receptor for bile acids. Treatment of cells expressing this GPCR with bile acids induces the production of intracellular cAMP, activation of a MAP kinase signaling pathway, and internalization of the receptor. The receptor is implicated in the suppression of macrophage functions and regulation of energy homeostasis by bile acids.

One effect of this receptor is to activate deiodinases which convert the prohormone thyroxine (T₄) to the active hormone triiodothyronine (T₃). T₃ in turn activates the thyroid hormone receptor which increases metabolic rate.

Bile Acid Effects on TGR5

Bile acid binds to the TGR5 receptor which increases the secretion of GLP-1. GLP-1 increases glucose-induced insulin secretion, satiety, and pancreatic beta cell production (responsible for insulin secretion). GLP-1 is also used in medications to treat type 2 diabetes.

GLP-1 undergoes heightened production through 2 pathways. The first pathway is the activation of Adenylyl cyclase and cAMP which begins a secondary messenger cascade to release GLP-1. The second pathway entails the increase in mitochondrial activity in response to nutrients like glucose and fatty acids which causes an increase in the ATP to ADP ratio. This leads to the inactivation of ATP-sensitive potassium channels that causes the cell membrane to depolarize. This depolarization causes an increase in voltage-gated calcium channel activity, sending a flood of calcium ions which triggers a cascade of events leading to increased GLP-1 secretion.

Extraintestinal Activation of TGR5 Receptors by Bile Acids

Bile acid's ability to act as an antagonist for TGR5 receptors located outside of the gastrointestinal tract means it has the ability to escape the tract and travel to these various regions. Primary bile acids are synthesized by hepatocytes in the liver and get conjugated with Taurine or glycine before they are stored in the gall bladder for stimulated secretion. Upon the presence of fats and proteins in the duodenum from the diet, these primary bile acids get secreted into the intestine where they are converted into secondary bile acids. 95% of these bile acids get reabsorbed into the liver for recirculation, of which 10% escapes this enterohepatic circulation and enters the systemic circulation. It is through their presence in the serum that they are able to get to various other organs where transporters and channels located at their membranes and barriers allow them to access the TGR5 receptors.

References

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2. ^ GRCm38: Ensembl release 89: ENSMUSG00000064272 – Ensembl, May 2017
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7. Maruyama T, Miyamoto Y, Nakamura T, Tamai Y, Okada H, Sugiyama E, Nakamura T, Itadani H, Tanaka K (2002-11-15). "Identification of membrane-type receptor for bile acids (M-BAR)". Biochemical and Biophysical Research Communications. 298 (5): 714–719. doi:10.1016/S0006-291X(02)02550-0. ISSN 0006-291X. PMID 12419312.
8. Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ (2005-06-01). "International Union of Pharmacology. XLVI. G Protein-Coupled Receptor List". Pharmacological Reviews. 57 (2): 279–288. doi:10.1124/pr.57.2.5. ISSN 0031-6997. PMID 15914470.
9. Wang H, Chen J, Hollister K, Sowers LC, Forman BM (May 1999). "Endogenous Bile Acids Are Ligands for the Nuclear Receptor FXR/BAR". Molecular Cell. 3 (5): 543–553. doi:10.1016/s1097-2765(00)80348-2. ISSN 1097-2765. PMID 10360171.
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11. Duboc H, Taché Y, Hofmann AF (April 2014). "The bile acid TGR5 membrane receptor: From basic research to clinical application". Digestive and Liver Disease. 46 (4): 302–312. doi:10.1016/j.dld.2013.10.021. ISSN 1590-8658. PMC 5953190. PMID 24411485.
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14. "Entrez Gene: GPBAR1 G protein-coupled bile acid receptor 1".
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18. Lun W, Yan Q, Guo X, Zhou M, Bai Y, He J, Cao H, Che Q, Guo J, Su Z (2024-02-01). "Mechanism of action of the bile acid receptor TGR5 in obesity". Acta Pharmaceutica Sinica B. 14 (2): 468–491. doi:10.1016/j.apsb.2023.11.011. ISSN 2211-3835. PMC 10840437. PMID 38322325.
19. Meloni AR, DeYoung MB, Lowe C, Parkes DG (January 2013). "GLP -1 receptor activated insulin secretion from pancreatic β-cells: mechanism and glucose dependence". Diabetes, Obesity and Metabolism. 15 (1): 15–27. doi:10.1111/j.1463-1326.2012.01663.x. ISSN 1462-8902. PMC 3556522. PMID 22776039.
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Further reading

• Takeda S, Kadowaki S, Haga T, et al. (2002). "Identification of G protein-coupled receptor genes from the human genome sequence". FEBS Lett. 520 (1–3): 97–101. Bibcode:2002FEBSL.520...97T. doi:10.1016/S0014-5793(02)02775-8. PMID 12044878. S2CID 7116392.
• Maruyama T, Miyamoto Y, Nakamura T, et al. (2003). "Identification of membrane-type receptor for bile acids (M-BAR)". Biochem. Biophys. Res. Commun. 298 (5): 714–9. doi:10.1016/S0006-291X(02)02550-0. PMID 12419312.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Kawamata Y, Fujii R, Hosoya M, et al. (2003). "A G protein-coupled receptor responsive to bile acids". J. Biol. Chem. 278 (11): 9435–40. doi:10.1074/jbc.M209706200. PMID 12524422.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Watanabe M, Houten SM, Mataki C, et al. (2006). "Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation". Nature. 439 (7075): 484–9. Bibcode:2006Natur.439..484W. doi:10.1038/nature04330. PMID 16400329. S2CID 4429032.
• Thomas SM, Bhola NE, Zhang Q, et al. (2007). "Cross-talk between G protein-coupled receptor and epidermal growth factor receptor signaling pathways contributes to growth and invasion of head and neck squamous cell carcinoma". Cancer Res. 66 (24): 11831–9. doi:10.1158/0008-5472.CAN-06-2876. PMID 17178880.
• Yasuda H, Hirata S, Inoue K, et al. (2007). "Involvement of membrane-type bile acid receptor M-BAR/TGR5 in bile acid-induced activation of epidermal growth factor receptor and mitogen-activated protein kinases in gastric carcinoma cells". Biochem. Biophys. Res. Commun. 354 (1): 154–9. doi:10.1016/j.bbrc.2006.12.168. PMID 17214962.
• Keitel V, Reinehr R, Gatsios P, et al. (2007). "The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells". Hepatology. 45 (3): 695–704. doi:10.1002/hep.21458. PMID 17326144. S2CID 24892239.

External links

• "Bile Acid Receptor". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2016-03-03. Retrieved 2007-11-01.
• GPBAR1+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

• Genes on human chromosome 2
• G protein-coupled receptors