T1R2 - Taste receptor type 1 member 2 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 ''TAS1R2''

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 ...

. The sweet taste receptor is predominantly formed as a dimer of T1R2 and T1R3 by which different organisms sense this taste. In songbirds, however, the T1R2 monomer does not exist, and they sense the sweet taste through the umami taste receptor (T1R1 and T1R3) as a result of an evolutionary change that it has undergone.

Structure and molecular function

Both T1R2 and T1R3 receptors belongs to the class C

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 ...

family that features a common structure comprised a large extracellular domain, called the venus flytrap domain (VFD), which is connected to a 7-helix TMD by a cysteine-rich domain (CRD). The canonical activation mechanism of class C GPCRs follows a multiple-step process that requires communication between the VFDs (housing the orthosteric-binding site) and the TMDs via the CRDs. Although the main binding site for most sweet compounds was found to reside in the VFT domain of T1R2, the T1R2 protein is not functional without formation of the 2+3 heterodimer.Yousif, Ragheed Hussam, et al. "Exploring the Molecular Interactions between Neoculin and the Human Sweet Taste Receptors through Computational Approaches." ''Sains Malaysiana'' 49.3 (2020): 517-525. APA Natural sweeteners interact with the orthosteric binding pocket, either of T1R2 or T1R3. The closure of the T1R2 extracellular domain involves the rotation of both T1R2 and T1R3 VFDs. The signal is then transmitted to the TMDs via the CRDs. It has also been shown that sweet proteins modulate the receptor by interacting with the CRD. Some artificial sweeteners as well as the inhibitor of the sweet taste receptor –

lactisole Lactisole is the sodium salt and commonly supplied form of 2-(4-methoxy phenoxy)propionic acid, a natural carboxylic acid found in roasted coffee beans. Like gymnemic acid, it has the property of masking sweet flavors and is used for this purpo ...

, were shown to interact with the allosteric binding sites of one of the sub-units in the TMD. A''TAS1R2'' and ''

TAS1R1 Taste receptor type 1 member 1 is a protein that in humans is encoded by the ''TAS1R1'' gene. Structure The protein encoded by the ''TAS1R1'' gene is a G protein-coupled receptor with seven trans-membrane domains and is a component of the hete ...

'' genes, is their spontaneous activity in the absence of the extracellular domains and binding ligands. This may mean that the extracellular domain regulates function of the receptor by preventing spontaneous action as well as binding to activating ligands such as

sucrose Sucrose, a disaccharide, is a sugar composed of glucose and fructose subunits. It is produced naturally in plants and is the main constituent of white sugar. It has the molecular formula . For human consumption, sucrose is extracted and refined ...

Ligands

The T1R2+3 receptor has been shown to respond to natural sugars

sorbitol Sorbitol (), less commonly known as glucitol (), is a sugar alcohol with a sweet taste which the human body metabolizes slowly. It can be obtained by reduction of glucose, which changes the converted aldehyde group (−CHO) to a primary alco ...

and

fructose Fructose (), or fruit sugar, is a Ketose, ketonic monosaccharide, simple sugar found in many plants, where it is often bonded to glucose to form the disaccharide sucrose. It is one of the three dietary monosaccharides, along with glucose and gal ...

, and to the artificial sweeteners

saccharin Saccharin, also called saccharine, benzosulfimide, or E954, or used in saccharin sodium or saccharin calcium forms, is a non-nutritive artificial sweetener. Saccharin is a sultam that is about 500 times sweeter than sucrose, but has a bitter or ...

acesulfame potassium Acesulfame potassium (, or ), also known as acesulfame K or Ace K, is a synthetic calorie-free sugar substitute (artificial sweetener) often marketed under the trade names Sunett and Sweet One. In the European Union, it is known under the E n ...

dulcin Dulcin is an artificial sweetener about 250 times sweeter than sugar, discovered in 1883 by the Polish chemist Józef (Joseph) Berlinerblau (27 August 1859 – 1935). It was first mass-produced about seven years later. Although it was discovere ...

, guanidinoacetic acid,

cyclamate Cyclamate is an artificial sweetener. It is 30–50 times sweeter than sucrose (table sugar), making it the least potent of the commercially used artificial sweeteners. It is often used with other artificial sweeteners, especially saccharin; the ...

sucralose Sucralose is an artificial sweetener and sugar substitute. In the European Union, it is also known under the E number E955. It is produced by chlorination of sucrose, selectively replacing three of the hydroxy groups—in the C1 a ...

alitame Alitame is an aspartic acid-containing dipeptide sweetener. It was developed by Pfizer in the early 1980s and currently marketed in some countries under the brand name Aclame. Most dipeptides are not sweet, but the unexpected discovery of asparta ...

, neotame and neohesperidin dihydrochalcone (NHDC). Research initially suggested that rat receptors did not respond to many other natural and artificial sugars, such as

glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...

and

aspartame Aspartame is an artificial non-saccharide sweetener commonly used as a sugar substitute in foods and beverages. 200 times sweeter than sucrose, it is a methyl ester of the aspartic acid/phenylalanine dipeptide with brand names NutraSwe ...

, leading to the conclusion that there must be more than one type of sweet taste receptor. Contradictory evidence, however, suggested that cells expressing the human T1R2+3 receptor showed sensitivity to both

and

but cells expressing the rat T1R2+3 receptor were only slightly activated by

and showed no

activation. These results are inconclusive about the existence of another sweet taste receptor, but show that the T1R2+3 receptors are responsible for a wide variety of different sweet tastes. Finally, T1R2+3 responses to non-sugar natural sweeteners such as steviol glycosides from the leaves of the Stevia plant and sweet proteins like thaumatin, monellin, and brazzein. Another surprising ligand of the T1R2+3 is D2O, also known as heavy water which was shown to activate the human T1R2+3 receptor.

Signal transduction

T1R2 and T1R1 receptors have been shown to bind to

G protein G proteins, also known as guanine nucleotide-binding proteins, are a Protein family, family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell (biology), ...

s, most often the

gustducin Gustducin is a G protein associated with taste and the gustatory system, found in some taste receptor cells. Research on the discovery and isolation of gustducin is recent. It is known to play a large role in the transduction of bitter, sweet ...

Gα subunit, although a gusducin knock-out has shown small residual activity. T1R2 and T1R1 have also been shown to activate Gαo and Gαi protein subunits. This suggests that T1R1 and T1R2 are

G protein-coupled receptors 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 protein family, group of evoluti ...

that inhibit

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 ...

s to decrease

cyclic guanosine monophosphate Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP. Its most likely mechanism of action is activation of intracellular protein kinases in ...

(cGMP) levels in

taste receptor A taste receptor or tastant is a type of cellular receptor that facilitates the sensation of taste. When food or other substances enter the mouth, molecules interact with saliva and are bound to taste receptors in the oral cavity and other locat ...

s. Research done by creating knock-outs of common channels activated by sensory G-protein

second messenger systems 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 ...

has also shown a connection between sweet taste perception and the

phosphatidylinositol Phosphatidylinositol or inositol phospholipid is a biomolecule. It was initially called "inosite" when it was discovered by Léon Maquenne and Johann Joseph von Scherer in the late 19th century. It was discovered in bacteria but later also found ...

(PIP2) pathway. The nonselective cation

Transient Receptor Potential Transient receptor potential channels (TRP channels) are a group of ion channels located mostly on the plasma membrane of numerous animal cell types. Most of these are grouped into two broad groups: Group 1 includes TRPC ( "C" for canonical), TRP ...

channel TRPM5 has been shown to correlate with both umami and sweet taste. Also, the

phospholipase A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C, and D, which are distinguished by the type of reaction which they catalyze: *Phospholipase ...

PLCβ2 was shown to similarly correlate with umami and sweet taste. This suggests that activation of the G-protein pathway and subsequent activation of PLC β2 and the TRPM5 channel in these taste cells functions to activate the cell.

Location and innervation

T1R2+3 expressing cells are found in

circumvallate papilla Lingual papillae (: papilla, ) are small structures on the upper surface of the tongue that give it its characteristic rough texture. The four types of papillae on the human tongue have different structures and are accordingly classified as circum ...

e and

foliate papilla Lingual papillae (: papilla, ) are small structures on the upper surface of the tongue that give it its characteristic rough texture. The four types of papillae on the human tongue have different structures and are accordingly classified as circum ...

e near the back of the

tongue The tongue is a Muscle, muscular organ (anatomy), organ in the mouth of a typical tetrapod. It manipulates food for chewing and swallowing as part of the digestive system, digestive process, and is the primary organ of taste. The tongue's upper s ...

and

palate The palate () is the roof of the mouth in humans and other mammals. It separates the oral cavity from the nasal cavity. A similar structure is found in crocodilians, but in most other tetrapods, the oral and nasal cavities are not truly sep ...

taste receptor cells in the roof of the mouth. These cells are shown to

synapse In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...

upon the

chorda tympani Chorda tympani is a branch of the facial nerve that carries gustatory (taste) sensory innervation from the front of the tongue and parasympathetic ( secretomotor) innervation to the submandibular and sublingual salivary glands. Chorda tymp ...

and

glossopharyngeal nerve The glossopharyngeal nerve (), also known as the ninth cranial nerve, cranial nerve IX, or simply CN IX, is a cranial nerve that exits the brainstem from the sides of the upper Medulla oblongata, medulla, just anterior (closer to the nose) to t ...

s to send their signals to the brain. T1R and T2R (bitter) channels are not expressed together in

taste bud Taste buds are clusters of taste receptor cells, which are also known as gustatory cells. The taste receptors are located around the small structures known as papillae found on the upper surface of the tongue, soft palate, upper esophagus, ...

References

External links

TAS1R2 Gene

TASTE RECEPTOR TYPE 1, MEMBER 2; TAS1R2
{{NLM content Human taste receptors