TheG protein-coupled bile acid receptor 1 (GPBAR1) also known asG-protein coupled receptor 19 (GPCR19),membrane-type receptor for bile acids (M-BAR) orTakeda G protein-coupled receptor 5 (TGR5) is aprotein that in humans is encoded by theGPBAR1gene.[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.
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]
TGR5 receptors are primarily located ingastrointestinal tracts where bile acid functions are most prevalent.[10] They can also be found throughout the body, including thenervous system,immune system, and variousmuscle groups, aiding in the tasks that are relevant to their respective locations.[11]
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 elicitsecond 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 theG protein-coupled receptor (GPCR) superfamily. As mentioned, this protein functions as a cell surface receptor forbile acids. Treatment of cells expressing this GPCR with bile acids induces the production of intracellularcAMP, activation of aMAP kinase signaling pathway, and internalization of the receptor. The receptor is implicated in the suppression ofmacrophage functions and regulation of energy homeostasis by bile acids.[14]
Bile acid binds to the TGR5 receptor which increases the secretion ofGLP-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 treattype 2 diabetes.[20]
GLP-1 undergoes heightened production through 2 pathways. The first pathway is the activation ofAdenylyl 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 ofcalcium ions which triggers a cascade of events leading to increased GLP-1 secretion.[26]
Extraintestinal Activation of TGR5 Receptors by Bile Acids
Bile acid's ability to act as an antagonist for TGR5 receptors located outside of thegastrointestinal tract means it has the ability to escape the tract and travel to these various regions. Primary bile acids are synthesized byhepatocytes in the liver[27] and get conjugated with Taurine or glycine before they are stored in thegall bladder for stimulated secretion.[28] Upon the presence of fats and proteins in theduodenum 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 theliver for recirculation,[31] of which 10% escapes thisenterohepatic circulation and enters thesystemic circulation.[32] It is through their presence in theserum 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.
^Wang H, Tan YZ, Mu RH, Tang SS, Liu X, Xing SY, et al. (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.PMID33536132.S2CID227165118.
^Maruyama T, Miyamoto Y, Nakamura T, Tamai Y, Okada H, Sugiyama E, et al. (November 2002). "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.PMID12419312.
^Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, et al. (June 2005). "International Union of Pharmacology. XLVI. G protein-coupled receptor list".Pharmacological Reviews.57 (2):279–288.doi:10.1124/pr.57.2.5.PMID15914470.
^Giaretta PR, Suchodolski JS, Blick AK, Steiner JM, Lidbury JA, Rech RR (January 2019). "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.PMID29999170.
^Drucker DJ (November 2024). "Efficacy and Safety of GLP-1 Medicines for Type 2 Diabetes and Obesity".Diabetes Care.47 (11):1873–1888.doi:10.2337/dci24-0003.PMID38843460.
^Gribble FM, Williams L, Simpson AK, Reimann F (May 2003). "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.PMID12716745.
Maruyama T, Miyamoto Y, Nakamura T, Tamai Y, Okada H, Sugiyama E, et al. (November 2002). "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.PMID12419312.
Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, et al. (January 2006). "Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation".Nature.439 (7075):484–489.Bibcode:2006Natur.439..484W.doi:10.1038/nature04330.PMID16400329.S2CID4429032.
Yasuda H, Hirata S, Inoue K, Mashima H, Ohnishi H, Yoshiba M (March 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".Biochemical and Biophysical Research Communications.354 (1):154–159.doi:10.1016/j.bbrc.2006.12.168.PMID17214962.
"Bile Acid Receptor".IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived fromthe original on 2016-03-03. Retrieved2007-11-01.
