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G protein-coupled bile acid receptor

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GPBAR1
Identifiers
AliasesGPBAR1, BG37, GPCR19, GPR131, M-BAR, TGR5, G protein-coupled bile acid receptor, G protein-coupled bile acid receptor 1
External IDsOMIM: 610147; MGI: 2653863; HomoloGene: 18125; GeneCards: GPBAR1; OMA:GPBAR1 - orthologs
Orthologs
SpeciesHumanMouse
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 MbChr 1: 74.32 – 74.32 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5][6] 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

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TGR5 receptors were first discovered by Takaharu Maruyama in 2002.[7] It was the first membrane bound G protein coupled receptor that was discovered for faster bile acid signaling.[8] 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).[9]

Location

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TGR5 receptors are primarily located in gastrointestinal tracts where bile acid functions are most prevalent.[10] 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.[11]

Function

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G-Protein Coupled Receptor working mechanism. The binding of an antagonist to the receptor binding cite, causes an exchange of the GDP, bound to the alpha subunit, with GTP. This activates the subunit allowing it to dissociate from its counterpart, the beta-gama subunit. These separated subunits go on to independently activate other second messenger systems like the cAMP which is activated by the alpha subunit acting on adenylyl cyclase. The GTP on the alpha subunit hydrolyzes back to GDP, allowing its re-association with the beta-gamma subunit.

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.[12] It is also a receptor for other agonists, including activating various other pathways responsible for responses like inflammation.[13]

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.[14]

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.[15][16]

Bile Acid Effects on TGR5

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Bile acid binds to the TGR5 receptor which increases the secretion of GLP-1.[17][18] GLP-1 increases glucose-induced insulin secretion, satiety, and pancreatic beta cell production (responsible for insulin secretion).[19] GLP-1 is also used in medications to treat type 2 diabetes.[20]

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.[21][22] 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.[23] This leads to the inactivation of ATP-sensitive potassium channels that causes the cell membrane to depolarize.[24][25] 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.[26]

Extraintestinal Activation of TGR5 Receptors by Bile Acids

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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[27] and get conjugated with Taurine or glycine before they are stored in the gall bladder for stimulated secretion.[28] Upon the presence of fats and proteins in the duodenum from the diet,[29] these primary bile acids get secreted into the intestine where they are converted into secondary bile acids.[30] 95% of these bile acids get reabsorbed into the liver for recirculation,[31] of which 10% escapes this enterohepatic circulation and enters the systemic circulation.[32] It is through their presence in the serum that they are able to get to various other organs where transporters and channels[33] located at their membranes and barriers allow them to access the TGR5 receptors.

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000179921 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000064272 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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 (11): 9435–40. doi:10.1074/jbc.M209706200. PMID 12524422.
  6. ^ Wang H, Tan YZ, Mu RH, Tang SS, Liu X, Xing SY, Long Y, Yuan DH, Hong H (June 2021). "Takeda G Protein-Coupled Receptor 5 Modulates Depression-like Behaviors via Hippocampal CA3 Pyramidal Neurons Afferent to Dorsolateral Septum". Biological Psychiatry. 89 (11): 1084–1095. doi:10.1016/j.biopsych.2020.11.018. PMID 33536132. S2CID 227165118.
  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.
  10. ^ Giaretta PR, Suchodolski JS, Blick AK, Steiner JM, Lidbury JA, Rech RR (October 2018). "Distribution of bile acid receptor TGR5 in the gastrointestinal tract of dogs". Histology and Histopathology. 34 (1): 69–79. doi:10.14670/HH-18-025. ISSN 0213-3911.
  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.
  12. ^ 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.
  13. ^ Guo C, Chen WD, Wang YD (2016-12-26). "TGR5, Not Only a Metabolic Regulator". Frontiers in Physiology. 7: 646. doi:10.3389/fphys.2016.00646. ISSN 1664-042X. PMC 5183627. PMID 28082913.
  14. ^ "Entrez Gene: GPBAR1 G protein-coupled bile acid receptor 1".
  15. ^ 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 (7075): 484–9. Bibcode:2006Natur.439..484W. doi:10.1038/nature04330. PMID 16400329. S2CID 4429032.
  16. ^ Baxter JD, Webb P (2006). "Metabolism: bile acids heat things up". Nature. 439 (7075): 402–3. Bibcode:2006Natur.439..402B. doi:10.1038/439402a. PMID 16437098. S2CID 45562883.
  17. ^ Brighton CA, Rievaj J, Kuhre RE, Glass LL, Schoonjans K, Holst JJ, Gribble FM, Reimann F (2015-11-01). "Bile Acids Trigger GLP-1 Release Predominantly by Accessing Basolaterally Located G Protein–Coupled Bile Acid Receptors". Endocrinology. 156 (11): 3961–3970. doi:10.1210/en.2015-1321. ISSN 0013-7227. PMC 4606749. PMID 26280129.
  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.
  20. ^ Drucker DJ (2024-06-06). "Efficacy and Safety of GLP-1 Medicines for Type 2 Diabetes and Obesity". Diabetes Care. 47 (11): 1873–1888. doi:10.2337/dci24-0003. ISSN 0149-5992. PMID 38843460.
  21. ^ Doyle ME, Egan JM (March 2007). "Mechanisms of action of glucagon-like peptide 1 in the pancreas". Pharmacology & Therapeutics. 113 (3): 546–593. doi:10.1016/j.pharmthera.2006.11.007. PMC 1934514. PMID 17306374.
  22. ^ Ramos LS, Zippin JH, Kamenetsky M, Buck J, Levin LR (September 2008). "Glucose and GLP-1 stimulate cAMP production via distinct adenylyl cyclases in INS-1E insulinoma cells". The Journal of General Physiology. 132 (3): 329–338. doi:10.1085/jgp.200810044. ISSN 1540-7748. PMC 2518727. PMID 18695009.
  23. ^ Thomas C, Gioiello A, Noriega L, Strehle A, Oury J, Rizzo G, Macchiarulo A, Yamamoto H, Mataki C, Pruzanski M, Pellicciari R, Auwerx J, Schoonjans K (September 2009). "TGR5-Mediated Bile Acid Sensing Controls Glucose Homeostasis". Cell Metabolism. 10 (3): 167–177. doi:10.1016/j.cmet.2009.08.001. PMC 2739652. PMID 19723493.
  24. ^ Gribble FM, Williams L, Simpson AK, Reimann F (2003-05-01). "A Novel Glucose-Sensing Mechanism Contributing to Glucagon-Like Peptide-1 Secretion From the GLUTag Cell Line". Diabetes. 52 (5): 1147–1154. doi:10.2337/diabetes.52.5.1147. ISSN 0012-1797.
  25. ^ Kuhre RE, Gribble FM, Hartmann B, Reimann F, Windeløv JA, Rehfeld JF, Holst JJ (2014-04-01). "Fructose stimulates GLP-1 but not GIP secretion in mice, rats, and humans". American Journal of Physiology-Gastrointestinal and Liver Physiology. 306 (7): G622–G630. doi:10.1152/ajpgi.00372.2013. ISSN 0193-1857. PMC 3962593. PMID 24525020.
  26. ^ Tolhurst G, Reimann F, Gribble FM (2009). "Nutritional regulation of glucagon-like peptide-1 secretion". The Journal of Physiology. 587 (1): 27–32. doi:10.1113/jphysiol.2008.164012. ISSN 1469-7793. PMC 2670019. PMID 19001044.
  27. ^ Chiang JY (2013), "Bile Acid Metabolism and Signaling", Comprehensive Physiology, 3 (3), John Wiley & Sons, Ltd: 1191–1212, doi:10.1002/cphy.c120023, ISBN 978-0-470-65071-4, PMC 4422175, PMID 23897684
  28. ^ Yeo XY, Tan LY, Chae WR, Lee DY, Lee YA, Wuestefeld T, Jung S (2023-02-02). "Liver's influence on the brain through the action of bile acids". Frontiers in Neuroscience. 17. doi:10.3389/fnins.2023.1123967. ISSN 1662-453X. PMC 9932919. PMID 36816113.
  29. ^ Banales JM, Prieto J, Medina JF (2006-06-14). "Cholangiocyte anion exchange and biliary bicarbonate excretion". World Journal of Gastroenterology. 12 (22): 3496–3511. doi:10.3748/wjg.v12.i22.3496. PMC 4087566. PMID 16773707.
  30. ^ Guzior DV, Quinn RA (2021-06-14). "Review: microbial transformations of human bile acids". Microbiome. 9 (1): 140. doi:10.1186/s40168-021-01101-1. ISSN 2049-2618. PMC 8204491. PMID 34127070.
  31. ^ Hirschfield GM, Heathcote EJ, Gershwin ME (November 2010). "Pathogenesis of Cholestatic Liver Disease and Therapeutic Approaches". Gastroenterology. 139 (5): 1481–1496. doi:10.1053/j.gastro.2010.09.004. ISSN 0016-5085. PMID 20849855.
  32. ^ Dawson PA, Lan T, Rao A (2009-12-01). "Bile acid transporters". Journal of Lipid Research. 50 (12): 2340–2357. doi:10.1194/jlr.R900012-JLR200. ISSN 0022-2275. PMC 2781307. PMID 19498215.
  33. ^ Roda A, Minutello A, Angellotti MA, Fini A (August 1990). "Bile acid structure-activity relationship: evaluation of bile acid lipophilicity using 1-octanol/water partition coefficient and reverse phase HPLC". Journal of Lipid Research. 31 (8): 1433–1443. doi:10.1016/S0022-2275(20)42614-8. ISSN 0022-2275. PMID 2280184.

Further reading

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

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