Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

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.

DOI： 10.3390/nu15132941

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Communications Biology  

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.

DOI： 10.1038/s42003-023-04705-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cell and Tissue Research  

Mammalian taste bud cells are composed of several distinct cell types and differentiated from surrounding tongue epithelial cells. However, the detailed mechanisms underlying their differentiation have yet to be elucidated. In the present study, we examined an Ascl1-expressing cell lineage using circumvallate papillae (CVP) of newborn mice and taste organoids (three-dimensional self-organized tissue cultures), which allow studying the differentiation of taste bud cells in fine detail ex vivo. Using lineage-tracing analysis, we observed that Ascl1 lineage cells expressed type II and III taste cell markers both CVP of newborn mice and taste organoids. However, the coexpression rate in type II cells was lower than that in type III cells. Furthermore, we found that the generation of the cells which express type II and III cell markers was suppressed in taste organoids lacking Ascl1-expressing cells. These findings suggest that Ascl1-expressing precursor cells can differentiate into both type III and a subset of type II taste cells.

DOI： 10.1007/s00441-023-03756-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Scientific Reports  

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.

DOI： 10.1038/s41598-022-25755-5

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Otorhinolaryngology-Head and Neck Surgery  

<p>　Taste is an important sense that is associated with appetite and food intake. Although many studies have been reported on taste detection tests in patients with taste disorders, few studies have been conducted in healthy subjects.</p><p>　The Iwaki Health Promotion Project is a large-scale epidemiological survey of local residents. In the present study, participants in Project 2019 were tested for sweet, salty, sour, and bitter taste thresholds, and 1027 participants for whom data were available were included in the analysis.</p><p>　A comparison of the taste thresholds among the age groups showed that the sour and salty tastes thresholds increased significantly with age, and the thresholds for all tastes was significantly lower in women than in men. In addition, decreased serum zinc levels were not necessarily associated with decreased taste, but decreased serum zinc levels and decreased taste were more frequently observed in the elderly. There were quite a few patients who were not aware of any taste disorder, even though they had a decreased sense of taste on examination. This indicates that there are potential patients with taste disorders.</p>

DOI： 10.3950/jibiinkotokeibu.125.9_1375

CiNii Research

Language：Japanese   Publisher：(一社)日本耳鼻咽喉科頭頸部外科学会  

味覚は食欲や摂食内容と関連する重要な感覚である.これまで,味覚障害患者を対象とした味覚試験は多数報告されているが,健常者を対象としたものは少ない.われわれは,一般地域住民を対象とした大規模疫学調査である岩木健康増進プロジェクトの2019年度の参加者を対象に,全口腔法により甘味,塩味,酸味,苦味の閾値を調査し,データの得られた1,027名について解析を行った.年齢層別に味覚閾値を比較したところ,高齢者ほど酸味と塩味の閾値が有意に上昇しており,男女間では女性の方が全味質で有意に閾値が低かった.また血清亜鉛値の低下は必ずしも味覚閾値上昇には結びつかなかったものの,血清亜鉛値の低下と味覚閾値上昇を来している者は高齢者で多く認められた.検査上で味覚閾値上昇を認めるにもかかわらず味覚障害の自覚がない者もおり,潜在的な味覚障害患者が存在することが示唆された.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J07551&link_issn=&doc_id=20220928410008&doc_link_id=%2Fdz0tokei%2F2022%2F012509%2F008%2F1375-1383%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdz0tokei%2F2022%2F012509%2F008%2F1375-1383%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bbrc.2021.04.022

Language：Others   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.3390/ijms21238958

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s40496-020-00266-2

Language：Others   Publishing type：Research paper (scientific journal)  

© 2020, The Author(s). Taste information is detected by taste cells and then transmitted to the brain through the taste nerve fibers. According to our previous data, there may be specific coding of taste quality between taste cells and nerve fibers. However, the molecular mechanisms underlying this coding specificity remain unclear. The purpose of this study was to identify candidate molecules that may regulate the specific coding. GeneChip analysis of mRNA isolated from the mice taste papillae and taste ganglia revealed that 14 members of the cadherin superfamily, which are important regulators of synapse formation and plasticity, were expressed in both tissues. Among them, protocadherin-20 (Pcdh20) was highly expressed in a subset of taste bud cells, and co-expressed with taste receptor type 1 member 3 (T1R3, a marker of sweet- or umami-sensitive taste cells) but not gustducin or carbonic anhydrase-4 (markers of bitter/sweet- and sour-sensitive taste cells, respectively) in circumvallate papillae. Furthermore, Pcdh20 expression in taste cells occurred later than T1R3 expression during the morphogenesis of taste papillae. Thus, Pcdh20 may be involved in taste quality-specific connections between differentiated taste cells and their partner neurons, thereby acting as a molecular tag for the coding of sweet and/or umami taste.

DOI： 10.1038/s41598-020-58991-8

Language：Japanese  

Language：Others   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.3390/nu11092251

Language：Others   Publishing type：Research paper (scientific journal)  

© 2017 IBRO 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 Cβ2 (PLCβ2) 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 PLCβ2. 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 PLCβ2 are indispensable for eliciting bitter taste responses of gustducin-positive taste cells.

DOI： 10.1016/j.neuroscience.2017.10.047

Language：English   Publishing type：Research paper (scientific journal)  

© 2017 Yoshida, Shin, Yasumatsu, Takai, Inoue, Shigemura, Takiguchi, Nakamura and Ninomiya. Cholecystokinin (CCK) is a gut hormone released from enteroendocrine cells. CCK functions as an anorexigenic factor by acting on CCK receptors expressed on the vagal afferent nerve and hypothalamus with a synergistic interaction between leptin. In the gut, tastants such as amino acids and bitter compounds stimulate CCK release from enteroendocrine cells via activation of taste transduction pathways. CCK is also expressed in taste buds, suggesting potential roles of CCK in taste signaling in the peripheral taste organ. In the present study, we focused on the function of CCK in the initial responses to taste stimulation. CCK was coexpressed with type II taste cell markers such as Ga-gustducin, phospholipase Cß2, and transient receptor potential channel M5. Furthermore, a small subset (~30%) of CCK-expressing taste cells expressed a sweet/umami taste receptor component, taste receptor type 1 member 3, in taste buds. Because type II taste cells are sweet, umami or bitter taste cells, the majority of CCK-expressing taste cells may be bitter taste cells. CCK-A and -B receptors were expressed in both taste cells and gustatory neurons. CCK receptor knockout mice showed reduced neural responses to bitter compounds compared with wild-type mice. Consistently, intravenous injection of CCK-Ar antagonist lorglumide selectively suppressed gustatory nerve responses to bitter compounds. Intravenous injection of CCK-8 transiently increased gustatory nerve activities in a dose-dependent manner whereas administration of CCK-8 did not affect activities of bitter-sensitive taste cells. Collectively, CCK may be a functionally important neurotransmitter or neuromodulator to activate bitter nerve fibers in peripheral taste tissues.

DOI： 10.3389/fphys.2017.00866

Language：Others  

© 2016 Elsevier Inc. All rights reserved. Taste receptor cells sense various chemical compounds in foods and transmit these signals through gustatory nerve fibers to the central nervous system. These sensory signals are vitally important for life; they provide information about which prospective foods are nutritious and warnings as to those that are noxious. Recent studies have revealed the involvement of multifarious bioactive peptides, many of which are primarily identified organs such as the gastrointestinal tract, in the modulation of taste responses. These peptides affect peripheral taste responsiveness of animals and play important roles in the regulation of feeding behavior and the maintenance of homeostasis. In this chapter, we discuss the various functions of peptide signaling in the peripheral taste system.

DOI： 10.1016/B978-0-12-801694-7.00017-2

Language：Others  

© 2015 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved. Background Several studies have demonstrated that some gut peptides known to be important in energy metabolism are expressed in mouse taste bud cells. However, the functions of these peptides in taste cells are still largely unknown. In the gut, one of these peptides, glucagon-like peptide-1 (GLP-1), which is known as the insulinotropic gut peptide, is secreted from enteroendocrine L-cells, which express as many taste molecules as those on the tongue. These taste transduction molecules are suggested to be involved in GLP-1 secretion from L-cells in response to various nutrient stimuli. GLP-1 is reported to function as a neurotransmitter via activation of its receptors expressed on the vagus nerve, thereby regulating insulin secretion. Highlight Consistent with this evidence from the gastrointestinal tract, recent studies have demonstrated that GLP-1 is secreted from mouse taste cells in response to taste compounds such as sugars, artificial sweeteners, and long-chain fatty acids. GLP-1 secreted from taste cells may activate particular types of gustatory nerve fibers because they express GLP-1 receptors and respond to GLP-1 administered via the femoral vein. Conclusion GLP-1 released from taste cells may be involved in transmission of sweet and lipid signals, thereby impacting animalsfeeding behavior in response to these important nutrient factors.

DOI： 10.1016/j.job.2015.09.002

Language：Others   Publishing type：Research paper (scientific journal)  

© FASEB. Five fundamental taste qualities (sweet, bitter, salty, sour, umami) are sensed by dedicated taste cells (TCs) that relay quality information to gustatory nerve fibers. In peripheral taste signaling pathways, ATP has been identified as a functional neurotransmitter, but it remains to be determined how specificity of different taste qualities is maintained across synapses. Recent studies demonstrated that some gut peptides are released from taste buds by prolonged application of particular taste stimuli, suggesting their potential involvement in taste information coding. In this study, we focused on the function of glucagon-like peptide-1 (GLP-1) in initial responses to taste stimulation. GLP-1 receptor (GLP-1R) null mice had reduced neural and behavioral responses specifically to sweet compounds compared to wild-type (WT) mice. Some sweet responsive TCs expressed GLP-1 and its receptors were expressed in gustatory neurons. GLP-1 was released immediately from taste bud cells in response to sweet compounds but not to other taste stimuli. Intravenous administration of GLP-1 elicited transient responses in a subset of sweet-sensitive gustatory nerve fibers but did not affect other types of fibers, and this response was suppressed by pre-administration of the GLP-1R antagonist Exendin-4(3-39). Thus GLP-1 may be involved in normal sweet taste signal transmission in mice.

DOI： 10.1096/fj.14-265355

Language：Japanese   Publishing type：Research paper (other academic)  

Language：Others   Publishing type：Research paper (scientific journal)  

The distinctive umami taste elicited by l-glutamate and some other amino acids is thought to be initiated by G-protein-coupled receptors. Proposed umami receptors include heteromers of taste receptor type 1, members 1 and 3 (T1R1+T1R3), and metabotropic glutamate receptors 1 and 4 (mGluR1 and mGluR4). Multiple lines of evidence support the involvement of T1R1+T1R3 in umami responses of mice. Although several studies suggest the involvement of receptors other than T1R1+T1R3 in umami, the identity of those receptors remains unclear. Here, we examined taste responsiveness of umami-sensitive chorda tympani nerve fibres from wild-type mice and mice genetically lacking T1R3 or its downstream transduction molecule, the ion channel TRPM5. Our results indicate that single umami-sensitive fibres in wild-type mice fall into two major groups: sucrose-best (S-type) and monopotassium glutamate (MPG)-best (M-type). Each fibre type has two subtypes; one shows synergism between MPG and inosine monophosphate (S1, M1) and the other shows no synergism (S2, M2). In both T1R3 and TRPM5 null mice, S1-type fibres were absent, whereas S2-, M1- and M2-types remained. Lingual application of mGluR antagonists selectively suppressed MPG responses of M1- and M2-type fibres. These data suggest the existence of multiple receptors and transduction pathways for umami responses in mice. Information initiated from T1R3-containing receptors may be mediated by a transduction pathway including TRPM5 and conveyed by sweet-best fibres, whereas umami information from mGluRs may be mediated by TRPM5-independent pathway(s) and conveyed by glutamate-best fibres. © 2012 The Authors. The Journal of Physiology © 2012 The Physiological Society.

DOI： 10.1113/jphysiol.2011.211920

Language：Others   Publishing type：Research paper (scientific journal)  

In taste bud cells, glutamate may elicit two types of responses, as an umami tastant and as a neurotransmitter. Glutamate applied to apical membrane of taste cells would elicit taste responses whereas glutamate applied to basolateral membrane may act as a neurotransmitter. Using restricted stimulation to apical or basolateral membrane of taste cells, we examined responses of taste cells to glutamate stimulation, separately. Apical application of monosodium glutamate (MSG, 0.3 M) increased firing frequency in some of mouse fungiform taste cells that evoked action potentials. These cells were tested with other basic taste compounds, NaCl (salty), saccharin (sweet), HCl (sour), and quinine (bitter). MSG-sensitive taste cells could be classified into sweet-best (S-type), MSG-best (M-type), and NaCl or other electrolytes-best (N- or E/H-type) cells. Furthermore, S- and M-type could be classified into two sub-types according to the synergistic effect between MSG and inosine-5'-monophosphate (S1, M1 with synergism; S2, M2 without synergism). Basolateral application of glutamate (100 μM) had almost no effect on the mean spontaneous firing rates in taste cells. However, about 10% of taste cells tested showed transient increases in spontaneous firing rates (>mean + 2 standard deviation) after basolateral application of glutamate. These results suggest the existence of multiple types of umami-sensitive taste cells and the existence of glutamate receptor(s) on the basolateral membrane of a subset of taste cells.

DOI： 10.1007/s10571-011-9702-5

Language：English   Publishing type：Research paper (scientific journal)  

Gustatory signaling begins with taste receptor cells that express taste receptors. Recent molecular biological studies have identified taste receptors and transduction components for basic tastes (sweet, salty, sour, bitter, and umami). Activation of these receptor systems leads to depolarization and an increase in [Ca²⁺]_i in taste receptor cells. Then transmitters are released from taste cells and activate gustatory nerve fibers. The connection between taste cells and gustatory nerve fibers would be specific because there may be only limited divergence of taste information at the peripheral transmission. Recent studies have demonstrated that sweet taste information can be modulated by hormones or other endogenous factors that could act on their receptors in a specific group of taste cells. These peripheral modulations of taste information may influence preference behavior and food intake. This paper summarizes data on molecular mechanisms for detection and transduction of taste signals in taste bud cells, information transmission from taste cells to gustatory nerve fibers, and modulation of taste signals at peripheral taste organs, in particular for sweet taste, which may play important roles in regulating energy homeostasis.

DOI： 10.1248/bpb.33.1772

Event date： 2022.6

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