Taste receptor

The TAS1R1+TAS1R3 heterodimer receptor functions as an umami receptor, responding to L-amino acid binding, especially L-glutamate.[2] The umami taste is most frequently associated with the food additive monosodium glutamate (MSG) and can be enhanced through the binding of inosine monophosphate (IMP) and guanosine monophosphate (GMP) molecules.[13][14] TAS1R1+3 expressing cells are found mostly in the fungiform papillae at the tip and edges of the tongue and palate taste receptor cells in the roof of the mouth.[2] These cells are shown to synapse upon the chorda tympani nerves to send their signals to the brain, although some activation of the glossopharyngeal nerve has been found.[13][15]

Alternative candidate umami taste receptors include splice variants of metabotropic glutamate receptors, mGluR4 and mGluR1, and the NMDA receptor.[10][16][17][18]

During the evolution of songbirds, the umami taste receptor has undergone structural modifications in the ligand binding site, enabling these birds to sense the sweet taste by this receptor.[19]

The diagram above depicts the signal transduction pathway of the sweet taste. Object A is a taste bud, object B is one taste cell of the taste bud, and object C is the neuron attached to the taste cell. I. Part I shows the reception of a molecule. 1. Sugar, the first messenger, binds to a protein receptor on the cell membrane. II. Part II shows the transduction of the relay molecules. 2. G Protein-coupled receptors, second messengers, are activated. 3. G Proteins activate adenylate cyclase, an enzyme, which increases the cAMP concentration. Depolarization occurs. 4. The energy, from step 3, is given to activate the K+, potassium, protein channels.III. Part III shows the response of the taste cell. 5. Ca+, calcium, protein channels is activated.6. The increased Ca+ concentration activates neurotransmitter vesicles. 7. The neuron connected to the taste bud is stimulated by the neurotransmitters.

The TAS1R2+TAS1R3 heterodimer receptor functions as the sweet receptor by binding to a wide variety of sugars and sugar substitutes.[2][20] TAS1R2+3 expressing cells are found in circumvallate papillae and foliate papillae near the back of the tongue and palate taste receptor cells in the roof of the mouth.[2] These cells are shown to synapse upon the chorda tympani and glossopharyngeal nerves to send their signals to the brain.[10][15] The TAS1R3 homodimer also functions as a sweet receptor in much the same way as TAS1R2+3 but has decreased sensitivity to sweet substances. Natural sugars are more easily detected by the TAS1R3 receptor than sugar substitutes. This may help explain why sugar and artificial sweeteners have different tastes.[21] Genetic polymorphisms in TAS1R3 partly explain the difference in sweet taste perception and sugar consumption between people of African American ancestry and people of European and Asian ancestries.[22][23]

Sensing of the sweet taste has changed throughout the evolution of different animals. Mammals sense the sweet taste by transferring the signal through the heterodimer T1R2/T1R3, the sweet taste receptor. In birds, however, the T1R2 monomer does not exist and they sense the sweet taste through the heterodimer T1R1/T1R3, the umami taste receptor, which has gone through modifications during their evolution. A recently conducted study showed that along the evolution stages of songbirds, there was a decrease in the ability to sense the umami taste, and an increase in the ability to sense the sweet taste, whereas the primordial songbird parent could only sense the umami taste. Researchers found a possible explanation for this phenomenon to be a structural change in the ligand binding site of the umami receptor between the sweet taste sensing and non-sensing songbirds. It is assumed that a mutation in the binding site occurred over time, which allowed them to sense the sweet taste through the umami taste receptor.[19]

The TAS2R proteins (InterPro: IPR007960) function as bitter taste receptors.[24] There are 43 human TAS2R genes, each of which (excluding the five pseudogenes) lacks introns and codes for a GPCR protein.[10] These proteins, as opposed to TAS1R proteins, have short extracellular domains and are located in circumvallate papillae, palate, foliate papillae, and epiglottis taste buds, with reduced expression in fungiform papillae.[3][10] Though it is certain that multiple TAS2Rs are expressed in one taste receptor cell, it is still debated whether mammals can distinguish between the tastes of different bitter ligands.[3][10] Some overlap must occur, however, as there are far more bitter compounds than there are TAS2R genes. Common bitter ligands include cycloheximide, denatonium, PROP (6-n-propyl-2-thiouracil), PTC (phenylthiocarbamide), and β-glucopyranosides.[10]

Signal transduction of bitter stimuli is accomplished via the α-subunit of gustducin. This G protein subunit activates a taste phosphodiesterase and decreases cyclic nucleotide levels. Further steps in the transduction pathway are still unknown. The βγ-subunit of gustducin also mediates taste by activating IP₃ (inositol triphosphate) and DAG (diglyceride). These second messengers may open gated ion channels or may cause release of internal calcium.[25] Though all TAS2Rs are located in gustducin-containing cells, knockout of gustducin does not completely abolish sensitivity to bitter compounds, suggesting a redundant mechanism for bitter tasting[12] (unsurprising given that a bitter taste generally signals the presence of a toxin).[12] One proposed mechanism for gustducin-independent bitter tasting is via ion channel interaction by specific bitter ligands, similar to the ion channel interaction which occurs in the tasting of sour and salty stimuli.[10]

One of the best-researched TAS2R proteins is TAS2R38, which contributes to the tasting of both PROP and PTC. It is the first taste receptor whose polymorphisms are shown to be responsible for differences in taste perception. Current studies are focused on determining other such taste phenotype-determining polymorphisms.[10] More recent studies show that genetic polymorphisms in other bitter taste receptor genes influence bitter taste perception of caffeine, quinine and denatonium benzoate.[26]

The diagram depicted above shows the signal transduction pathway of the bitter taste. Bitter taste has many different receptors and signal transduction pathways. Bitter indicates poison to animals. It is most similar to sweet. Object A is a taste bud, object B is one taste cell, and object C is a neuron attached to object B. I. Part I is the reception of a molecule.1. A bitter substance such as quinine, is consumed and binds to G Protein-coupled receptors.II. Part II is the transduction pathway 2. Gustducin, a G protein second messenger, is activated. 3. Phosphodiesterase, an enzyme, is then activated. 4. Cyclic nucleotide, cNMP, is used, lowering the concentration 5. Channels such as the K+, potassium, channels, close.III. Part III is the response of the taste cell. 6. This leads to increased levels of Ca+. 7. The neurotransmitters are activated. 8. The signal is sent to the neuron.

It has been demonstrated that bitterness receptors (TAS2R) play an important role in an innate immune system of airway (nose and sinuses) ciliated epithelium tissues.[27] This innate immune system adds an "active fortress"[28] to the physical Immune system surface barrier. This fixed immune system is activated by the binding of ligands to specific receptors. These natural ligands are bacterial markers, for TAS2R38 example: acyl-homoserine lactones[29] or quinolones[30] produced by Pseudomonas aeruginosa. To defend against predators, some plants have produced mimic bacterial markers substances. These plant mimes are interpreted by the tongue, and the brain, as being bitterness. The fixed immune system receptors are identical to the bitter taste receptors, TAS2R. Bitterness substances are agonist of TAS2R fixed immune system. [27] The innate immune system uses nitric oxide and defensins which are capable of destroying bacteria, and also viruses.[31][32] These fixed innate immune systems (Active Fortresses) are known in other epithelial tissues than upper airway (nose, sinuses, trachea, bronchi), for example: breast (mammary epithelial cells), gut and also human skin (keratinocytes)[33] Bitter molecules, their associated bitter taste receptors, and the sequences and homology models of bitter taste receptors, are available via BitterDB.

Historically it was thought that the sour taste was produced solely when free hydrogen ions (H⁺) directly depolarised taste receptors. However, specific receptors for sour taste with other methods of action are now being proposed. The HCN channels were such a proposal; as they are cyclic nucleotide-gated channels. The two ion channels now suggested to contribute to sour taste are ASIC2 and TASK-1.

The diagram depicts the signal transduction pathway of the sour or salty taste. Object A is a taste bud, object B is a taste receptor cell within object A, and object C is the neuron attached to object B. I. Part I is the reception of hydrogen ions or sodium ions. 1. If the taste is sour, H+ ions, from an acidic substances, pass through their specific ion channel. Some can go through the Na+ channels. If the taste is salty Na+, sodium, molecules pass through the Na+ channels. Depolarization takes place II. Part II is the transduction pathway of the relay molecules.2. Cation, such as K+, channels are opened. III. Part III is the response of the cell. 3. An influx of Ca+ ions is activated.4. The Ca+ activates neurotransmitters. 5. A signal is sent to the neuron attached to the taste bud.

Various receptors have also been proposed for salty tastes, along with the possible taste detection of lipids, complex carbohydrates, and water. Evidence for these receptors had been unconvincing in most mammal studies. For example, the proposed ENaC receptor for sodium detection can only be shown to contribute to sodium taste in Drosophila.[10] However, proteolyzed forms of ENaC have been shown to function as a human salt taste receptor. Proteolysis is the process where a protein is cleaved. The mature form of ENaC is thought to be proteolyzed, however the characterization of which proteolyzed forms exist in which tissues is incomplete. Proteolysis of cells created to overexpress hetermulitmeric ENaC comprising alpha, beta and gamma subunits was used to identify compounds that selectively enhanced the activity of proteolyzed ENaC versus non-proteolyzed ENaC. Human sensory studies demonstrated that a compound that enhances proteolyzed ENaC functions to enhance the salty taste of table salt, or sodium chloride, confirming proteolyzed ENaC as the first human salt taste receptor.[34]

An enzyme connected to the sour receptor transmits information about carbonated water.[35]

A possible taste receptor for fat, CD36, has been identified.[36] CD36 has been localized to the circumvallate and foliate papillae, which are present in taste buds[37] and where lingual lipase is produced, and research has shown that the CD36 receptor binds long chain fatty acids.[38] Differences in the amount of CD36 expression in human subjects was associated with their ability to taste fats,[39] creating a case for the receptor's relationship to fat tasting. Further research into the CD36 receptor could be useful in determining the existence of a true fat-tasting receptor.

Free fatty acid receptor 4 (also termed GPR120) and to a much lesser extent free fatty acid receptor 1 (also termed GPR40)[40] have been implicated to respond to oral fat,[41] and their absence leads to reduced fat preference and reduced neuronal response to orally administered fatty acids.[42]

TRPM5 has been shown to be involved in oral fat response and identified as a possible oral fat receptor, but recent evidence presents it as primarily a downstream actor.[43][44]