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 Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''GPBAR1''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. 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 tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...

s where bile acid functions are most prevalent. They can also be found throughout the body, including the

nervous system In biology, the nervous system is the complex system, highly complex part of an animal that coordinates its behavior, actions and sense, sensory information by transmitting action potential, signals to and from different parts of its body. Th ...

immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...

, 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 system Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form of cell signaling, encompassing both first me ...

s 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 G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...

(GPCR) superfamily. As mentioned, this protein functions as a cell surface receptor for

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

s. Treatment of cells expressing this GPCR with bile acids induces the production of intracellular

cAMP Camp may refer to: Areas of confinement, imprisonment, or for execution * Concentration camp, an internment camp for political prisoners or politically targeted demographics, such as members of national or minority ethnic groups * Extermination ...

, activation of a

MAP kinase A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammato ...

signaling pathway, and internalization of the receptor. The receptor is implicated in the suppression of

macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

functions and regulation of energy homeostasis by bile acids. One effect of this receptor is to activate deiodinases which convert the

prohormone A prohormone is a committed precursor of a hormone consisting of peptide hormones synthesized together that has a minimal hormonal effect by itself because of its expression-suppressing structure, often created by protein folding and binding addit ...

thyroxine Thyroxine, also known as T4, is a hormone produced by the thyroid gland. It is the primary form of thyroid hormone found in the blood and acts as a prohormone of the more active thyroid hormone, triiodothyronine (T3). Thyroxine and its acti ...

(T₄) to the active hormone

triiodothyronine Triiodothyronine, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate. Production of T3 and its prohormone thyroxi ...

(T₃). T₃ in turn activates the

thyroid hormone receptor The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. TRs act as transcription factors, ultimately affecting the regulation of gene transcription and translation. These receptors also have ...

which increases

metabolic rate Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

Bile Acid Effects on TGR5

Bile acid binds to the TGR5 receptor which increases the secretion of

GLP-1 Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certai ...

. 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 Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...

. GLP-1 undergoes heightened production through 2 pathways. The first pathway is the activation of

Adenylyl cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...

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 Calcium ions (Ca2+) contribute to the physiology and biochemistry of organisms' cells. They play an important role in signal transduction pathways, where they act as a second messenger, in neurotransmitter release from neurons, in contraction ...

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

means it has the ability to escape the tract and travel to these various regions. Primary bile acids are synthesized by

hepatocyte A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein synthesis * Protein storage * Transformation of carbohydrates * Synthesis of cholesterol, bi ...

s in the liver and get conjugated with Taurine or glycine before they are stored in the

gall bladder In vertebrates, the gallbladder, also known as the cholecyst, is a small hollow organ where bile is stored and concentrated before it is released into the small intestine. In humans, the pear-shaped gallbladder lies beneath the liver, althoug ...

for stimulated secretion. Upon the presence of fats and proteins in the

duodenum The duodenum is the first section of the small intestine in most vertebrates, including mammals, reptiles, and birds. In mammals, it may be the principal site for iron absorption. The duodenum precedes the jejunum and ileum and is the shortest p ...

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 The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

for recirculation, of which 10% escapes this

enterohepatic circulation Enterohepatic circulation is the circulation of biliary acids, bilirubin, drugs or other substances from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte and transport back to the liver. Enterohepa ...

and enters the

systemic circulation In vertebrates, the circulatory system is a organ system, system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of ...

. It is through their presence in the

serum Serum may refer to: Biology and pharmacology *Serum (blood), plasma from which the clotting proteins have been removed **Antiserum, blood serum with specific antibodies for passive immunity *Serous fluid, any clear bodily fluid Places *Serum, Ind ...

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

External links

* * {{NLM content G protein-coupled receptors