G protein-coupled bile acid receptor

Last updated
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
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 Mb Chr 1: 74.32 – 74.32 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/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.

Contents

History

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

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

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. GPCR-Zyklus.png
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

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

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.

Related Research Articles

<span class="mw-page-title-main">Insulin</span> Peptide hormone

Insulin is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (INS) gene. It is the main anabolic hormone of the body. It regulates the metabolism of carbohydrates, fats, and protein by promoting the absorption of glucose from the blood into cells of the liver, fat, and skeletal muscles. In these tissues the absorbed glucose is converted into either glycogen, via glycogenesis, or fats (triglycerides), via lipogenesis; in the liver, glucose is converted into both. Glucose production and secretion by the liver are strongly inhibited by high concentrations of insulin in the blood. Circulating insulin also affects the synthesis of proteins in a wide variety of tissues. It is thus an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules in the cells. Low insulin in the blood has the opposite effect, promoting widespread catabolism, especially of reserve body fat.

<span class="mw-page-title-main">Glucagon</span> Peptide hormone

Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose. It is produced from proglucagon, encoded by the GCG gene.

<span class="mw-page-title-main">Alpha cell</span> Glucagon secreting cell

Alpha cells (α-cells) are endocrine cells that are found in the Islets of Langerhans in the pancreas. Alpha cells secrete the peptide hormone glucagon in order to increase glucose levels in the blood stream.

<span class="mw-page-title-main">Gastric inhibitory polypeptide</span> Mammalian protein found in Homo sapiens

Gastric inhibitory polypeptide(GIP), also known as glucose-dependent insulinotropic polypeptide, is an inhibiting hormone of the secretin family of hormones. While it is a weak inhibitor of gastric acid secretion, its main role, being an incretin, is to stimulate insulin secretion.

<span class="mw-page-title-main">Bile acid</span> Steroid acid found predominantly in the bile of mammals and other vertebrates

Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts.

<span class="mw-page-title-main">GLUT4</span> Protein

Glucose transporter type 4 (GLUT4), also known as solute carrier family 2, facilitated glucose transporter member 4, is a protein encoded, in humans, by the SLC2A4 gene. GLUT4 is the insulin-regulated glucose transporter found primarily in adipose tissues and striated muscle. The first evidence for this distinct glucose transport protein was provided by David James in 1988. The gene that encodes GLUT4 was cloned and mapped in 1989.

<span class="mw-page-title-main">Glucagon-like peptide-1</span> Gastrointestinal peptide hormone involved in glucose homeostasis

Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certain neurons within the nucleus of the solitary tract in the brainstem upon food consumption. The initial product GLP-1 (1–37) is susceptible to amidation and proteolytic cleavage, which gives rise to the two truncated and equipotent biologically active forms, GLP-1 (7–36) amide and GLP-1 (7–37). Active GLP-1 protein secondary structure includes two α-helices from amino acid position 13–20 and 24–35 separated by a linker region.

<span class="mw-page-title-main">Glucagon receptor</span> Protein-coding gene in the species Homo sapiens

The glucagon receptor is a 62 kDa protein that is activated by glucagon and is a member of the class B G-protein coupled family of receptors, coupled to G alpha i, Gs and to a lesser extent G alpha q. Stimulation of the receptor results in the activation of adenylate cyclase and phospholipase C and in increased levels of the secondary messengers intracellular cAMP and calcium. In humans, the glucagon receptor is encoded by the GCGR gene.

<span class="mw-page-title-main">Cholesterol 7 alpha-hydroxylase</span> Protein-coding gene in the species Homo sapiens

Cholesterol 7 alpha-hydroxylase also known as cholesterol 7-alpha-monooxygenase or cytochrome P450 7A1 (CYP7A1) is an enzyme that in humans is encoded by the CYP7A1 gene which has an important role in cholesterol metabolism. It is a cytochrome P450 enzyme, which belongs to the oxidoreductase class, and converts cholesterol to 7-alpha-hydroxycholesterol, the first and rate limiting step in bile acid synthesis.

<span class="mw-page-title-main">Glucagon-like peptide-1 receptor</span> Receptor activated by peptide hormone GLP-1

The glucagon-like peptide-1 receptor (GLP1R) is a G protein-coupled receptor (GPCR) found on beta cells of the pancreas and on neurons of the brain. It is involved in the control of blood sugar level by enhancing insulin secretion. In humans it is synthesised by the gene GLP1R, which is present on chromosome 6. It is a member of the glucagon receptor family of GPCRs. GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1, and one transmembrane (TMD) domain that binds the N-terminal region of GLP-1. In the TMD domain there is a fulcrum of polar residues that regulates the biased signaling of the receptor while the transmembrane helical boundaries and extracellular surface are a trigger for biased agonism.

<span class="mw-page-title-main">Gastric inhibitory polypeptide receptor</span> Protein-coding gene in the species Homo sapiens

The gastric inhibitory polypeptide receptor (GIP-R), also known as the glucose-dependent insulinotropic polypeptide receptor, is a protein that in humans is encoded by the GIPR gene.

<span class="mw-page-title-main">Free fatty acid receptor 1</span> Protein-coding gene in the species Homo sapiens

Free fatty acid receptor 1 (FFAR1), also known as G-protein coupled receptor 40 (GPR40), is a rhodopsin-like G-protein coupled receptor that is coded by the FFAR1 gene. This gene is located on the short arm of chromosome 19 at position 13.12. G protein-coupled receptors reside on their parent cells' surface membranes, bind any one of the specific set of ligands that they recognize, and thereby are activated to trigger certain responses in their parent cells. FFAR1 is a member of a small family of structurally and functionally related GPRs termed free fatty acid receptors (FFARs). This family includes at least three other FFARs viz., FFAR2, FFAR3, and FFAR4. FFARs bind and thereby are activated by certain fatty acids.

<span class="mw-page-title-main">Free fatty acid receptor 3</span> Protein-coding gene in the species Homo sapiens

Free fatty acid receptor 3 protein is a G protein coupled receptor that in humans is encoded by the FFAR3 gene. GPRs reside on cell surfaces, bind specific signaling molecules, and thereby are activated to trigger certain functional responses in their parent cells. FFAR3 is a member of the free fatty acid receptor group of GPRs that includes FFAR1, FFAR2, and FFAR4. All of these FFARs are activated by fatty acids. FFAR3 and FFAR2 are activated by certain short-chain fatty acids (SC-FAs), i.e., fatty acids consisting of 2 to 6 carbon atoms whereas FFFAR1 and FFAR4 are activated by certain fatty acids that are 6 to more than 21 carbon atoms long. Hydroxycarboxylic acid receptor 2 is also activated by a SC-FA that activate FFAR3, i.e., butyric acid.

<span class="mw-page-title-main">Free fatty acid receptor 2</span> Protein-coding gene in the species Homo sapiens

Free fatty acid receptor 2 (FFAR2), also known as G-protein coupled receptor 43 (GPR43), is a rhodopsin-like G-protein coupled receptor (GPCR) encoded by the FFAR2 gene. In humans, the FFAR2 gene is located on the long arm of chromosome 19 at position 13.12 (19q13.12).

<span class="mw-page-title-main">GPR119</span> Protein-coding gene in humans

G protein-coupled receptor 119 also known as GPR119 is a G protein-coupled receptor that in humans is encoded by the GPR119 gene.

<span class="mw-page-title-main">Free fatty acid receptor 4</span> Protein-coding gene in the species Homo sapiens

Free Fatty acid receptor 4 (FFAR4), also termed G-protein coupled receptor 120 (GPR120), is a protein that in humans is encoded by the FFAR4 gene. This gene is located on the long arm of chromosome 10 at position 23.33. G protein-coupled receptors reside on their parent cells' surface membranes, bind any one of the specific set of ligands that they recognize, and thereby are activated to trigger certain responses in their parent cells. FFAR4 is a rhodopsin-like GPR in the broad family of GPRs which in humans are encoded by more than 800 different genes. It is also a member of a small family of structurally and functionally related GPRs that include at least three other free fatty acid receptors (FFARs) viz., FFAR1, FFAR2, and FFAR3. These four FFARs bind and thereby are activated by certain fatty acids.

<span class="mw-page-title-main">RAPGEF4</span> Protein-coding gene in the species Homo sapiens

Rap guanine nucleotide exchange factor (GEF) 4 (RAPGEF4), also known as exchange protein directly activated by cAMP 2 (EPAC2) is a protein that in humans is encoded by the RAPGEF4 gene.

<span class="mw-page-title-main">Chemerin</span> Protein-coding gene in the species Homo sapiens

Chemerin, also known as retinoic acid receptor responder protein 2 (RARRES2), tazarotene-induced gene 2 protein (TIG2), or RAR-responsive protein TIG2 is a protein that in humans is encoded by the RARRES2 gene.

The insulin transduction pathway is a biochemical pathway by which insulin increases the uptake of glucose into fat and muscle cells and reduces the synthesis of glucose in the liver and hence is involved in maintaining glucose homeostasis. This pathway is also influenced by fed versus fasting states, stress levels, and a variety of other hormones.

GLP1 poly-agonist peptides are a class of drugs that activate multiple peptide hormone receptors including the glucagon-like peptide-1 (GLP-1) receptor. These drugs are developed for the same indications as GLP-1 receptor agonists—especially obesity, type 2 diabetes, and non-alcoholic fatty liver disease. They are expected to provide superior efficacy with fewer adverse effects compared to GLP-1 mono-agonists, which are dose-limited by gastrointestinal disturbances. The effectiveness of multi-receptor agonists could possibly equal or exceed that of bariatric surgery. The first such drug to receive approval is tirzepatide, a dual agonist of GLP-1 and GIP receptors.

References

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  2. 1 2 3 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.
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  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.
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  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.
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  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".
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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.
  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.
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  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.
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  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.

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