Relationship between olfactory and gustatory functions: The Iwaki health promotion project 2019.

OBJECTIVE: Olfactory and gustatory functions are important sensory aspects in humans. Although they are believed to influence each other, their interrelationship is not well understood. In this study, we aimed to investigate the relationship between the olfactory and gustatory functions based on the results of a large-scale epidemiological study (Iwaki Health Promotion Project) of the general local population. METHODS: We analyzed 565 participants who underwent taste and olfactory tests in the 2019 Iwaki Project. Gustatory function was tested for four taste qualities (sweet, sour, salty, and bitter) using whole-mouth taste tests. Olfactory function was tested using the University of Pennsylvania Smell Identification Test modified for Japanese (UPSIT-J). We evaluated sex-related differences between olfactory and gustatory functions and the effects of various factors on olfactory identification using multivariate analysis. Furthermore, we compared the percentage of accurate UPSIT-J responses between the normal and hypogeusia groups. We also analyzed the effects of taste and olfactory functions on eating. RESULTS: Olfactory and gustatory functions were lower in men than in women. Among the four taste qualities, salty taste was the most closely associated with olfactory identification ability, with lower olfactory scores of salty taste in the hypogeusia group than in the normal group. Moreover, the hyposmia group had higher daily salt intake than the normal olfaction group in women. CONCLUSION: These results suggest that olfactory identification tests may be useful in predicting elevated salt cognitive thresholds, leading to a reduction in salt intake, which may contribute to hypertension prevention.

The Antiarrhythmic Drug Flecainide Enhances Aversion to HCl in Mice.

Drug-induced taste disorders reduce quality of life, but little is known about the molecular mechanisms by which drugs induce taste disturbances. In this study, we investigated the short-term and long-term effects of the antiarrhythmic drug flecainide, which is known to cause taste dysfunction. Analyses of behavioral responses (licking tests) revealed that mice given a single intraperitoneal injection of flecainide exhibited a significant reduction in preference for a sour tastant (HCl) but not for other taste solutions (NaCl, quinine, sucrose, KCl and monopotassium glutamate) when compared with controls. Mice administered a single dose of flecainide also had significantly higher taste nerve responses to HCl but not to other taste solutions. Compared with controls, mice administered flecainide once-daily for 30 d showed a reduced preference for HCl without any changes in the behavioral responses to other taste solutions. The electrophysiological experiments using HEK293T cells transiently expressing otopetrin-1 (Otop1; the mouse sour taste receptor) showed that flecainide did not alter the responses to HCl. Taken together, our results suggest that flecainide specifically enhances the response to HCl in mice during short-term and long-term administration. Although further studies will be needed to elucidate the molecular mechanisms, these findings provide new insights into the pathophysiology of drug-induced taste disorders.

The G protein-coupled receptor GPRC5C is a saccharide sensor with a novel 'off' response.

GPRC5C is an orphan G protein-coupled receptor (GPCR) that belongs to the class C GPCR family. Although GPRC5C is expressed in various organs, its function and ligand are still undetermined. We found that GPRC5C is expressed in mouse taste cells, enterocytes, and pancreatic α-cells. In functional imaging assays, HEK293 cells heterologously expressing GPRC5C and the chimeric G protein α subunit Gα16-gust44 showed robust intracellular Ca2+ increases in response to monosaccharides, disaccharides, and a sugar alcohol, but not an artificial sweetener or sweet-tasting amino acid. Notably, Ca2+ increases occurred after washout, not during stimulation. Our findings suggest that GPRC5C has receptor properties which lead to novel 'off' responses to saccharide detachment and may work as an internal or external chemosensor specifically tuned to natural sugars.

Adrenomedullin Enhances Mouse Gustatory Nerve Responses to Sugars via T1R-Independent Sweet Taste Pathway.

On the tongue, the T1R-independent pathway (comprising glucose transporters, including sodium-glucose cotransporter (SGLT1) and the KATP channel) detects only sugars, whereas the T1R-dependent (T1R2/T1R3) pathway can broadly sense various sweeteners. Cephalic-phase insulin release, a rapid release of insulin induced by sensory signals in the head after food-related stimuli, reportedly depends on the T1R-independent pathway, and the competitive sweet taste modulators leptin and endocannabinoids may function on these two different sweet taste pathways independently, suggesting independent roles of two oral sugar-detecting pathways in food intake. Here, we examined the effect of adrenomedullin (ADM), a multifunctional regulatory peptide, on sugar sensing in mice since it affects the expression of SGLT1 in rat enterocytes. We found that ADM receptor components were expressed in T1R3-positive taste cells. Analyses of chorda tympani (CT) nerve responses revealed that ADM enhanced responses to sugars but not to artificial sweeteners and other tastants. Moreover, ADM increased the apical uptake of a fluorescent D-glucose derivative into taste cells and SGLT1 mRNA expression in taste buds. These results suggest that the T1R-independent sweet taste pathway in mouse taste cells is a peripheral target of ADM, and the specific enhancement of gustatory nerve responses to sugars by ADM may contribute to caloric sensing and food intake.

Prediction of dynamic allostery for the transmembrane domain of the sweet taste receptor subunit, TAS1R3.

The sweet taste receptor plays an essential role as an energy sensor by detecting carbohydrates. However, the dynamic mechanisms of receptor activation remain unclear. Here, we describe the interactions between the transmembrane domain of the G protein-coupled sweet receptor subunit, TAS1R3, and allosteric modulators. Molecular dynamics simulations reproduced species-specific sensitivity to ligands. We found that a human-specific sweetener, cyclamate, interacted with the mouse receptor as a negative allosteric modulator. Agonist-induced allostery during receptor activation was found to destabilize the intracellular part of the receptor, which potentially interfaces with the Gα subunit, through ionic lock opening. A common human variant (R757C) of the TAS1R3 exhibited a reduced response to sweet taste, in support of our predictions. Furthermore, histidine residues in the binding site acted as pH-sensitive microswitches to modulate the sensitivity to saccharin. This study provides important insights that may facilitate the prediction of dynamic activation mechanisms for other G protein-coupled receptors.

Cellular mechanisms of taste disturbance induced by the non-steroidal anti-inflammatory drug, diclofenac, in mice.

Drug-induced taste disorders are a serious problem in an aging society. This study investigated the mechanisms underlying taste disturbances induced by diclofenac, a non-steroidal anti-inflammatory drug that reduces pain and inflammation by inhibiting the synthesis of prostaglandins by cyclooxygenase enzymes (COX-1 and COX-2). RT-PCR analyses demonstrated the expression of genes encoding arachidonic acid pathway components such as COX-1, COX-2 and prostaglandin synthases in a subset of mouse taste bud cells. Double-staining immunohistochemistry revealed that COX-1 and cytosolic prostaglandin E synthase (cPGES) were co-expressed with taste receptor type-1 member-3 (T1R3), a sweet/umami receptor component, or gustducin, a bitter/sweet/umami-related G protein, in a subset of taste bud cells. Long-term administration of diclofenac reduced the expression of genes encoding COX-1, gustducin and cPGES in mouse taste buds and suppressed both the behavioral and taste nerve responses to sweet and umami taste stimuli but not to other tastants. Furthermore, diclofenac also suppressed the responses of both mouse and human sweet taste receptors (T1R2/T1R3, expressed in HEK293 cells) to sweet taste stimuli. These results suggest that diclofenac may suppress the activation of sweet and umami taste cells acutely via a direct action on T1R2/T1R3 and chronically via inhibition of the COX/prostaglandin synthase pathway inducing down-regulated expression of sweet/umami responsive components. This dual inhibition mechanism may underlie diclofenac-induced taste alterations in humans.

Bisphosphonate affects the behavioral responses to HCl by disrupting farnesyl diphosphate synthase in mouse taste bud and tongue epithelial cells.

Little is known about the molecular mechanisms underlying drug-induced taste disorders, which can cause malnutrition and reduce quality of life. One of taste disorders is known adverse effects of bisphosphonates, which are administered as anti-osteoporotic drugs. Therefore, the present study evaluated the effects of risedronate (a bisphosphonate) on taste bud cells. Expression analyses revealed that farnesyl diphosphate synthase (FDPS, a key enzyme in the mevalonate pathway) was present in a subset of mouse taste bud and tongue epithelial cells, especially type III sour-sensitive taste cells. Other mevalonate pathway-associated molecules were also detected in mouse taste buds. Behavioral analyses revealed that mice administered risedronate exhibited a significantly enhanced aversion to HCl but not for other basic taste solutions, whereas the taste nerve responses were not affected by risedronate. Additionally, the taste buds of mice administered risedronate exhibited significantly lower mRNA expression of desmoglein-2, an integral component of desmosomes. Taken together, these findings suggest that risedronate may interact directly with FDPS to inhibit the mevalonate pathway in taste bud and tongue epithelial cells, thereby affecting the expression of desmoglein-2 related with epithelial barrier function, which may lead to alterations in behavioral responses to HCl via somatosensory nerves.

In vitro and in silico characterization of adiponectin-receptor agonist dipeptides.

The aim of this study is to develop a dipeptide showing an adiponectin receptor 1 (AdipoR1) agonistic effect in skeletal muscle L6 myotubes. Based on the structure of the AdipoR1 agonist, AdipoRon, 15 synthetic dipeptides were targeted to promote glucose uptake in L6 myotubes. Tyr-Pro showed a significant increase in glucose uptake among the dipeptides, while other dipeptides, including Pro-Tyr, failed to exert this effect. Tyr-Pro induces glucose transporter 4 (Glut4) expression in the plasma membrane, along with adenosine monophosphate-activated protein kinase (AMPK) activation. In AdipoR1-knocked down cells, the promotion by Tyr-Pro was ameliorated, indicating that Tyr-Pro may directly interact with AdipoR1 as an agonist, followed by the activation of AMPK/Glut4 translocation in L6 myotubes. Molecular dynamics simulations revealed that a Tyr-Pro molecule was stably positioned in the two potential binding pockets (sites 1 and 2) of the seven-transmembrane receptor, AdipoR1, anchored in a virtual 1-palmitoyl-2-oleoyl-phosphatidylcholine membrane. In conclusion, we demonstrated the antidiabetic function of the Tyr-Pro dipeptide as a possible AdipoR1 agonist.

The Ile191Val is a partial loss-of-function variant of the TAS1R2 sweet-taste receptor and is associated with reduced glucose excursions in humans.

OBJECTIVE: Sweet taste receptors (STR) are expressed in the gut and other extra-oral tissues, suggesting that STR-mediated nutrient sensing may contribute to human physiology beyond taste. A common variant (Ile191Val) in the TAS1R2 gene of STR is associated with nutritional and metabolic outcomes independent of changes in taste perception. It is unclear whether this polymorphism directly alters STR function and how it may contribute to metabolic regulation. METHODS: We implemented a combination of in vitro biochemical approaches to decipher the effects of TAS1R2 polymorphism on STR function. Then, as proof-of-concept, we assessed its effects on glucose homeostasis in apparently healthy lean participants. RESULTS: The Ile191Val variant causes a partial loss of function of TAS1R2 through reduced receptor availability in the plasma membrane. Val minor allele carriers have reduced glucose excursions during an OGTT, mirroring effects previously seen in mice with genetic loss of function of TAS1R2. These effects were not due to differences in beta-cell function or insulin sensitivity. CONCLUSIONS: Our pilot studies on a common TAS1R2 polymorphism suggest that STR sensory function in peripheral tissues, such as the intestine, may contribute to the regulation of metabolic control in humans.

Gene expression profiling of α-gustducin-expressing taste cells in mouse fungiform and circumvallate papillae.

Taste buds are complex sensory organs embedded in the epithelium of fungiform papillae (FP) and circumvallate papillae (CV). The sweet, bitter, and umami tastes are sensed by type II taste cells that express taste receptors (Tas1rs and Tas2rs) coupled with the taste G-protein α-gustducin. Recent studies revealed that the taste response profiles of α-gustducin-expressing cells are different between FP and CV, but which genes could generate such distinctive cell characteristics are still largely unknown. We performed a comprehensive transcriptome analysis on α-gustducin-expressing cells in mouse FP and CV by single-cell RNA sequencing combined with fluorescence-activated cell sorting. Transcriptome profiles of the α-gustducin-expressing cells showed various expression patterns of taste receptors. Our clustering analysis defined the specific cell populations derived from FP or CV based on their distinct gene expression. Immunohistochemistry confirmed the specific expression of galectin-3, encoded by Lgals3, which was recognized as a differentially expressed gene in the transcriptome analysis. Our work provides fundamental knowledge toward understanding the genetic heterogeneity of type II cells, potentially revealing differential characterization of FP and CV taste bud cells.

Drinking Ice-Cold Water Reduces the Severity of Anticancer Drug-Induced Taste Dysfunction in Mice.

Taste disorders are common adverse effects of cancer chemotherapy that can reduce quality of life and impair nutritional status. However, the molecular mechanisms underlying chemotherapy-induced taste disorders remain largely unknown. Furthermore, there are no effective preventive measures for chemotherapy-induced taste disorders. We investigated the effects of a combination of three anticancer drugs (TPF: docetaxel, cisplatin and 5-fluorouracil) on the structure and function of mouse taste tissues and examined whether the drinking of ice-cold water after TPF administration would attenuate these effects. TPF administration significantly increased the number of cells expressing apoptotic and proliferative markers. Furthermore, TPF administration significantly reduced the number of cells expressing taste cell markers and the magnitudes of the responses of taste nerves to tastants. The above results suggest that anticancer drug-induced taste dysfunction may be due to a reduction in the number of taste cells expressing taste-related molecules. The suppressive effects of TPF on taste cell marker expression and taste perception were reduced by the drinking of ice-cold water. We speculate that oral cryotherapy with an ice cube might be useful for prophylaxis against anticancer drug-induced taste disorders in humans.

Identification of characteristic compounds of moderate volatility in breast cancer cell lines.

In this study, we were challenging to identify characteristic compounds in breast cancer cell lines. GC analysis of extracts from the culture media of breast cancer cell lines (MCF-7, SK-BR-3, and YMB-1) using a solid-phase Porapak Q extraction revealed that two compounds of moderate volatility, 1-hexadecanol and 5-(Z)-dodecenoic acid, were detected with markedly higher amount than those in the medium of fibroblast cell line (KMST-6). Furthermore, LC-TOF/MS analysis of the extracts clarified that in addition to the above two fatty acids, the amounts of five unsaturated fatty acids [decenoic acid (C10:1), decadienoic acid (C10:2), 5-(Z)-dodecenoic acid (C12:1), 5-(Z)-tetradecenoic acid (C14:1), and tetradecadienoic acid (C14:2)] in MCF-7 medium were higher than those in medium of KMST-6. Interestingly, H2O2-oxidation of 5-(Z)-dodecenoic acid and 5-(Z)-tetradecenoic acid produced volatile aldehydes that were reported as specific volatiles in breath from various cancer patients, such as heptanal, octanal, nonanal, decanal, 2-(E)-nonenal, and 2-(E)-octenal. Thus, we concluded that these identified compounds over-produced in breast cancer cells in this study could serve as potential precursors producing reported cancer-specific volatiles.

Effects of insulin signaling on mouse taste cell proliferation.

Expression of insulin and its receptor (IR) in rodent taste cells has been proposed, but exactly which types of taste cells express IR and the function of insulin signaling in taste organ have yet to be determined. In this study, we analyzed expression of IR mRNA and protein in mouse taste bud cells in vivo and explored its function ex vivo in organoids, using RT-PCR, immunohistochemistry, and quantitative PCR. In mouse taste tissue, IR was expressed broadly in taste buds, including in type II and III taste cells. With using 3-D taste bud organoids, we found insulin in the culture medium significantly decreased the number of taste cell and mRNA expression levels of many taste cell genes, including nucleoside triphosphate diphosphohydrolase-2 (NTPDase2), Tas1R3 (T1R3), gustducin, carbonic anhydrase 4 (CA4), glucose transporter-8 (GLUT8), and sodium-glucose cotransporter-1 (SGLT1) in a concentration-dependent manner. Rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR) signaling, diminished insulin's effects and increase taste cell generation. Altogether, circulating insulin might be an important regulator of taste cell growth and/or proliferation via activation of the mTOR pathway.

Expression of Renin-Angiotensin System Components in the Taste Organ of Mice.

The systemic renin-angiotensin system (RAS) is an important regulator of body fluid and sodium homeostasis. Angiotensin II (AngII) is a key active product of the RAS. We previously revealed that circulating AngII suppresses amiloride-sensitive salt taste responses and enhances the responses to sweet compounds via the AngII type 1 receptor (AT1) expressed in taste cells. However, the molecular mechanisms underlying the modulation of taste function by AngII remain uncharacterized. Here we examined the expression of three RAS components, namely renin, angiotensinogen, and angiotensin-converting enzyme-1 (ACE1), in mouse taste tissues. We found that all three RAS components were present in the taste buds of fungiform and circumvallate papillae and co-expressed with αENaC (epithelial sodium channel α-subunit, a salt taste receptor) or T1R3 (taste receptor type 1 member 3, a sweet taste receptor component). Water-deprived mice exhibited significantly increased levels of renin expression in taste cells (p < 0.05). These results indicate the existence of a local RAS in the taste organ and suggest that taste function may be regulated by both locally-produced and circulating AngII. Such integrated modulation of peripheral taste sensitivity by AngII may play an important role in sodium/calorie homeostasis.

Structural architecture of a dimeric class C GPCR based on co-trafficking of sweet taste receptor subunits.

Class C G protein-coupled receptors (GPCRs) are obligatory dimers that are particularly important for neuronal responses to endogenous and environmental stimuli. Ligand recognition through large extracellular domains leads to the reorganization of transmembrane regions to activate G protein signaling. Although structures of individual domains are known, the complete architecture of a class C GPCR and the mechanism of interdomain coupling during receptor activation are unclear. By screening a mutagenesis library of the human class C sweet taste receptor subunit T1R2, we enhanced surface expression and identified a dibasic intracellular retention motif that modulates surface expression and co-trafficking with its heterodimeric partner T1R3. Using a highly expressed T1R2 variant, dimerization sites along the entire subunit within all the structural domains were identified by a comprehensive mutational scan for co-trafficking with T1R3 in human cells. The data further reveal that the C terminus of the extracellular cysteine-rich domain needs to be properly folded for T1R3 dimerization and co-trafficking, but not for surface expression of T1R2 alone. These results guided the modeling of the T1R2-T1R3 dimer in living cells, which predicts a twisted arrangement of domains around the central axis, and a continuous folded structure between transmembrane domain loops and the cysteine-rich domains. These insights have implications for how conformational changes between domains are coupled within class C GPCRs.

Diurnal Variation of Sweet Taste Recognition Thresholds Is Absent in Overweight and Obese Humans.

Sweet taste thresholds are positively related to plasma leptin levels in normal weight humans: both show parallel diurnal variations and associations with postprandial glucose and insulin rises. Here, we tested whether this relationship also exists in overweight and obese (OW/Ob) individuals with hyperleptinemia. We tested 36 Japanese OW/Ob subjects (body mass index (BMI) > 25 kg/m²) for recognition thresholds for various taste stimuli at seven different time points from 8:00 a.m. to 10:00 p.m. using the staircase methodology, and measured plasma leptin, insulin, and blood glucose levels before each taste threshold measurement. We also used the homeostatic model assessment of insulin resistance (HOMA-IR) to evaluate insulin resistance. The results demonstrated that, unlike normal weight subjects, OW/Ob subjects showed no significant diurnal variations in the recognition thresholds for sweet stimuli but exhibited negative associations between the diurnal variations of both leptin and sweet recognition thresholds and the HOMA-IR scores. These findings suggest that in OW/Ob subjects, the basal leptin levels (~20 ng/mL) may already exceed leptin's effective concentration for the modulation of sweet sensitivity and that this leptin resistance-based attenuation of the diurnal variations of the sweet taste recognition thresholds may also be indirectly linked to insulin resistance in OW/Ob subjects.

Bitter Taste Responses of Gustducin-positive Taste Cells in Mouse Fungiform and Circumvallate Papillae.

Bitter taste serves as an important signal for potentially poisonous compounds in foods to avoid their ingestion. Thousands of compounds are estimated to taste bitter and presumed to activate taste receptor cells expressing bitter taste receptors (Tas2rs) and coupled transduction components including gustducin, phospholipase Cß2 (PLCß2) and transient receptor potential channel M5 (TRPM5). Indeed, some gustducin-positive taste cells have been shown to respond to bitter compounds. However, there has been no systematic characterization of their response properties to multiple bitter compounds and the role of transduction molecules in these cells. In this study, we investigated bitter taste responses of gustducin-positive taste cells in situ in mouse fungiform (anterior tongue) and circumvallate (posterior tongue) papillae using transgenic mice expressing green fluorescent protein in gustducin-positive cells. The overall response profile of gustducin-positive taste cells to multiple bitter compounds (quinine, denatonium, cyclohexamide, caffeine, sucrose octaacetate, tetraethylammonium, phenylthiourea, L-phenylalanine, MgSO4, and high concentration of saccharin) was not significantly different between fungiform and circumvallate papillae. These bitter-sensitive taste cells were classified into several groups according to their responsiveness to multiple bitter compounds. Bitter responses of gustducin-positive taste cells were significantly suppressed by inhibitors of TRPM5 or PLCß2. In contrast, several bitter inhibitors did not show any effect on bitter responses of taste cells. These results indicate that bitter-sensitive taste cells display heterogeneous responses and that TRPM5 and PLCß2 are indispensable for eliciting bitter taste responses of gustducin-positive taste cells.

Leptin suppresses sweet taste responses of enteroendocrine STC-1 cells.

Leptin is an important hormone that regulates food intake and energy homeostasis by acting on central and peripheral targets. In the gustatory system, leptin is known to selectively suppress sweet responses by inhibiting the activation of sweet sensitive taste cells. Sweet taste receptor (T1R2+T1R3) is also expressed in gut enteroendocrine cells and contributes to nutrient sensing, hormone release and glucose absorption. Because of the similarities in expression patterns between enteroendocrine and taste receptor cells, we hypothesized that they may also share similar mechanisms used to modify/regulate the sweet responsiveness of these cells by leptin. Here, we used mouse enteroendocrine cell line STC-1 and examined potential effect of leptin on Ca(2+) responses of STC-1 cells to various taste compounds. Ca(2+) responses to sweet compounds in STC-1 cells were suppressed by a rodent T1R3 inhibitor gurmarin, suggesting the involvement of T1R3-dependent receptors in detection of sweet compounds. Responses to sweet substances were suppressed by ⩾1ng/ml leptin without affecting responses to bitter, umami and salty compounds. This effect was inhibited by a leptin antagonist (mutant L39A/D40A/F41A) and by ATP gated K(+) (KATP) channel closer glibenclamide, suggesting that leptin affects sweet taste responses of enteroendocrine cells via activation of leptin receptor and KATP channel expressed in these cells. Moreover, leptin selectively inhibited sweet-induced but not bitter-induced glucagon-like peptide-1 (GLP-1) secretion from STC-1 cells. These results suggest that leptin modulates sweet taste responses of enteroendocrine cells to regulate nutrient sensing, hormone release and glucose absorption in the gut.

Intracellular acidification is required for full activation of the sweet taste receptor by miraculin.

Acidification of the glycoprotein, miraculin (MCL), induces sweet taste in humans, but not in mice. The sweet taste induced by MCL is more intense when acidification occurs with weak acids as opposed to strong acids. MCL interacts with the human sweet receptor subunit hTAS1R2, but the mechanisms by which the acidification of MCL activates the sweet taste receptor remain largely unexplored. The work reported here speaks directly to this activation by utilizing a sweet receptor TAS1R2 + TAS1R3 assay. In accordance with previous data, MCL-applied cells displayed a pH dependence with citric acid (weak acid) being right shifted to that with hydrochloric acid (strong acid). When histidine residues in both the intracellular and extracellular region of hTAS1R2 were exchanged for alanine, taste-modifying effect of MCL was reduced or abolished. Stronger intracellular acidification of HEK293 cells was induced by citric acid than by HCl and taste-modifying effect of MCL was proportional to intracellular pH regardless of types of acids. These results suggest that intracellular acidity is required for full activation of the sweet taste receptor by MCL.

Structure, function, and signaling of taste G-protein-coupled receptors.

Detection of tastes is critical for animals. Sweet, umami and bitter taste are mediated by G-protein-coupled receptors that are expressed in the taste receptor cells. TAS1Rs which belong to class C G-protein-coupled receptors form heterodimeric complexes to function as sweet (TAS1R2 + TAS1R3) or umami (TAS1R1 + TAS1R3) taste receptors. Umami taste is also considered to be mediated by mGluRs. TAS2Rs belong to class A G-protein-coupled receptors and are responsible for bitter taste. After activation of these receptors, their second messenger pathways lead to depolarization and intracellular calcium increase in taste receptor cells. Then, transmitter is released from taste receptor cells leading to activation of taste nerve fibers and taste information is sent to the central nervous system. Recent studies on heterologous expression system and molecular modeling lead to better understanding of binding site of TAS1Rs and TAS2Rs and molecular mechanisms for interaction between taste substances and these receptors. TAS1Rs and TAS2Rs have multiple and single binding sites for structurally diverse ligands, respectively. Sensitivities of these receptors are known to differ among individuals, strains, and species. In addition, some species abolish these receptors and signaling molecules. Here we focus on structure, function, signaling, polymorphism, and molecular evolution of the taste G-protein-coupled receptors.