研究者詳細 - 吉田　竜介

論文 - 吉田　竜介

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Dual functions of SNAP25 in mouse taste buds 査読

Kengo Horie, Kuanyu Wang, Hai Huang, Keiko Yasumatsu, Yuzo Ninomiya, Yoshihiro Mitoh, Ryusuke Yoshida

Journal of Physiology 2025年6月

Taste receptor type 1 member 3 in osteoclasts regulates osteoclastogenesis via detection of glucose 査読

Anna Yoshimura, Takuma Matsubara, Nao Kodama, Yoshimitsu Kakuta, Kazuma Yasuda, Ryusuke Yoshida, Osamu Kaminuma, Shuhei Hosomi, Hiroji Shinkawa, Quan Yuan, Tatsuo Kawamoto, Shoichiro Kokabu

Journal of Biological Chemistry 108273 - 108273 2025年2月

Exploring the Role of Ccn3 in Type III Cell of Mice Taste Buds 査読

Kuanyu Wang, Yoshihiro Mitoh, Kengo Horie, Ryusuke Yoshida

Journal of Neurochemistry 169 e16291 2024年12月

Salivary buffering capacity is correlated with umami but not sour taste sensitivity in healthy adult Japanese subjects 査読

Aiko Hyodo, Ayaka Mikami, Kengo Horie, Yoshihiro Mitoh, Yuzo Ninomiya, Seiji Iida, Ryusuke Yoshida

Archives of Oral Biology 165 106013 - 106013 2024年9月

The role of GABA in modulation of taste signaling within the taste bud 査読

Ayaka Mikami, Hai Huang, Aiko Hyodo, Kengo Horie, Keiko Yasumatsu, Yuzo Ninomiya, Yoshihiro Mitoh, Seiji Iida, Ryusuke Yoshida

Pflügers Archiv - European Journal of Physiology 2024年8月

担当区分：最終著者,　責任著者掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Science and Business Media LLC

Abstract

Taste buds contain 2 types of GABA-producing cells: sour-responsive Type III cells and glial-like Type I cells. The physiological role of GABA, released by Type III cells is not fully understood. Here, we investigated the role of GABA released from Type III cells using transgenic mice lacking the expression of GAD67 in taste bud cells (Gad67-cKO mice). Immunohistochemical experiments confirmed the absence of GAD67 in Type III cells of Gad67-cKO mice. Furthermore, no difference was observed in the expression and localization of cell type markers, ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2), gustducin, and carbonic anhydrase 4 (CA4) in taste buds between wild-type (WT) and Gad67-cKO mice. Short-term lick tests demonstrated that both WT and Gad67-cKO mice exhibited normal licking behaviors to each of the five basic tastants. Gustatory nerve recordings from the chorda tympani nerve demonstrated that both WT and Gad67-cKO mice similarly responded to five basic tastants when they were applied individually. However, gustatory nerve responses to sweet–sour mixtures were significantly smaller than the sum of responses to each tastant in WT mice but not in Gad67-cKO mice. In summary, elimination of GABA signalling by sour-responsive Type III taste cells eliminates the inhibitory cell–cell interactions seen with application of sour–sweet mixtures.

DOI： 10.1007/s00424-024-03007-x

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その他リンク： https://link.springer.com/article/10.1007/s00424-024-03007-x/fulltext.html

Mechanisms and Functions of Sweet Reception in Oral and Extraoral Organs 査読

Ryusuke Yoshida, Yuzo Ninomiya

International Journal of Molecular Sciences 25 ( 13 ) 7398 - 7398 2024年7月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI AG

The oral detection of sugars relies on two types of receptor systems. The first is the G-protein-coupled receptor TAS1R2/TAS1R3. When activated, this receptor triggers a downstream signaling cascade involving gustducin, phospholipase Cβ2 (PLCβ2), and transient receptor potential channel M5 (TRPM5). The second type of receptor is the glucose transporter. When glucose enters the cell via this transporter, it is metabolized to produce ATP. This ATP inhibits the opening of KATP channels, leading to cell depolarization. Beside these receptor systems, sweet-sensitive taste cells have mechanisms to regulate their sensitivity to sweet substances based on internal and external states of the body. Sweet taste receptors are not limited to the oral cavity; they are also present in extraoral organs such as the gastrointestinal tract, pancreas, and brain. These extraoral sweet receptors are involved in various functions, including glucose absorption, insulin release, sugar preference, and food intake, contributing to the maintenance of energy homeostasis. Additionally, sweet receptors may have unique roles in certain organs like the trachea and bone. This review summarizes past and recent studies on sweet receptor systems, exploring the molecular mechanisms and physiological functions of sweet (sugar) detection in both oral and extraoral organs.

DOI： 10.3390/ijms25137398

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Distribution of alpha‐synuclein in rat salivary glands 査読

Tomiko Nishitani, Yoshihiro Mitoh, Takehiro Yajima, Daisuke Tachiya, Tomohiro Hoshika, Tomohiro Fukunaga, Yoshihiro Nishitani, Ryusuke Yoshida, Itaru Mizoguchi, Hiroyuki Ichikawa, Tadasu Sato

The Anatomical Record 2024年1月

掲載種別：研究論文（学術雑誌）出版者・発行元：Wiley

Abstract

Expression of alpha‐synuclein (Syn), a presynaptic neuronal protein, was immunohistochemically examined in intact rat submandibular, sublingual, and lingual glands. The submandibular gland contained abundant periductal Syn‐immunoreactive (−ir) nerve fibers. Abundant Syn‐ir varicosities were present in acini of the sublingual and serous lingual glands. By confocal laser scanning microscopy, Syn‐ir nerve fibers around smooth muscle actin (SMA)‐ir cells alone were infrequent; however, those around aquaporin‐5 (AQP5)‐ir cells alone and both SMA‐ and AQP5‐ir cells were abundant in the sublingual and serous lingual glands. SMA‐ir cells were occasionally immunoreactive for toll‐like receptor 4, a Syn receptor. Syn‐ir nerve fibers contained tyrosine hydroxylase (TH) in the submandibular gland and choline acetyltransferase (ChAT) in all examined salivary glands. In the superior cervical (SCG), submandibular, and intralingual ganglia, sympathetic and parasympathetic neurons co‐expressed Syn with TH and ChAT, respectively. SCG neurons innervating the submandibular gland contained mostly Syn. In the thoracic spinal cord, 14.7% of ChAT‐ir preganglionic sympathetic neurons co‐expressed Syn. In the superior salivatory nucleus, preganglionic parasympathetic neurons projecting to the lingual nerve co‐expressed Syn and ChAT. The present findings indicate that released Syn acts on myoepithelial cells. Syn in pre‐ and post‐ganglionic neurons may regulate neurotransmitter release and salivary volume and composition.

DOI： 10.1002/ar.25395

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The antiarrhythmic drug flecainide enhances aversion to HCl in mice 査読

Yuko Kawabata, Shingo Takai, Keisuke Sanematsu, Ryusuke Yoshida, Fuminori Kawabata, Noriatsu Shigemura

eneuro ENEURO.0048 - 23.2023 2023年9月

掲載種別：研究論文（学術雑誌）出版者・発行元：Society for Neuroscience

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- 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 days 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 rarely altered the responses to HCl. Taken together, our results suggest that flecainide specifically enhances the response to HCl in mice during short- 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.

Significance Statement

Drug-induced taste disorders reduce quality of life and can lead to nutritional disturbances. However, little is known about its molecular mechanisms. We focused on the antiarrhythmic drug flecainide inducing “unpleasant or bad taste” in human patients. Mice administered a single dose of flecainide exhibited a reduced preference for and higher taste nerve responses to HCl, sour tastants specifically. Flecainide had little change in response to HCl in HEK293T cells expressing the sour taste receptor, proton channel otopetrin-1 (Otop1). Our results suggest that flecainide enhances the responses of sour-sensing taste cells to HCl. Although further studies will be needed to elucidate the molecular mechanisms, these findings provide new insights into the pathophysiology of drug-induced taste disorders.

DOI： 10.1523/eneuro.0048-23.2023

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Sensory Systems for Sugar-Induced Cephalic Phase Insulin Release 招待査読

Ryusuke Yoshida

Current Oral Health Reports 2023年8月

担当区分：筆頭著者,　責任著者掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Science and Business Media LLC

Abstract

Purpose of Review

This review aims to discuss and summarize the peripheral sensory mechanisms involved in the induction of the early phase of insulin release, known as cephalic phase insulin release (CPIR), triggered by stimuli related to food, particularly sugars.

Recent Findings

At least, two distinct systems on the tongue are responsible for detecting oral sugars. The first system involves the G-protein-coupled receptor Tas1r2/Tas1r3, which can detect not only sugars but also artificial sweeteners and sweet proteins. The second system relies on glucose transporters, specifically recognize and transport monosaccharides. The Tas1r2/Tas1r3 receptor utilizes a signal transduction pathway involving gustducin, phospholipase β2, and transient receptor potential channel M5 to depolarize taste cells. On the other hand, glucose transporters facilitate the transport of monosaccharides into cells, where their degradation produces ATP. This ATP inhibits the metabolic sensor K_ATP channel, ultimately leading to cell depolarization. Recent studies in mice have demonstrated that glucose transporters and K_ATP channels, rather than the Tas1r2/Tas1r3 receptor, are essential for the induction of CPIR.

Summary

The detection of sugars in the oral cavity relies on two essential mechanisms: the Tas1r2/Tas1r3 receptor and glucose transporters. Notably, oral glucose transporters are likely to play a significant role in the induction of sugar-induced CPIR. As a result, these two sugar detection systems may have distinct roles in maintaining energy homeostasis within the body.

DOI： 10.1007/s40496-023-00347-y

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その他リンク： https://link.springer.com/article/10.1007/s40496-023-00347-y/fulltext.html

Sugar signals from oral glucose transporters elicit cephalic-phase insulin release in mice 査読

Mitsuhito Takamori, Yoshihiro Mitoh, Kengo Horie, Masahiko Egusa, Takuya Miyawaki, Ryusuke Yoshida

The Journal of Physiological Sciences 73 ( 1 ) 2023年7月

担当区分：最終著者,　責任著者掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Science and Business Media LLC

Abstract

Cephalic-phase insulin release (CPIR) occurs before blood glucose increases after a meal. Although glucose is the most plausible cue to induce CPIR, peripheral sensory systems involved are not fully elucidated. We therefore examined roles of sweet sensing by a T1R3-dependent taste receptor and sugar sensing by oral glucose transporters in the oropharyngeal region in inducing CPIR. Spontaneous oral ingestion of glucose significantly increased plasma insulin 5 min later in wild-type (C57BL/6) and T1R3-knockout mice, but intragastric infusion did not. Oral treatment of glucose transporter inhibitors phlorizin and phloretin significantly reduced CPIR after spontaneous oral ingestion. In addition, a rapid increase in plasma insulin was significantly smaller in WT mice with spontaneous oral ingestion of nonmetabolizable glucose analog than in WT mice with spontaneous oral ingestion of glucose. Taken together, the T1R3-dependent receptor is not required for CPIR, but oral glucose transporters greatly contribute to induction of CPIR by sugars.

DOI： 10.1186/s12576-023-00875-3

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その他リンク： https://link.springer.com/article/10.1186/s12576-023-00875-3/fulltext.html

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

Shusuke Iwata, Ryusuke Yoshida, Shingo Takai, Keisuke Sanematsu, Noriatsu Shigemura, Yuzo Ninomiya

Nutrients 15 ( 13 ) 2941 - 2941 2023年6月

担当区分：筆頭著者掲載種別：研究論文（学術雑誌）出版者・発行元：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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Taste Responses and Ingestive Behaviors to Ingredients of Fermented Milk in Mice 査読

Yamase Yuko, Huang Hai, Mitoh Yoshihiro, Egusa Masahiko, Miyawaki Takuya, Yoshida Ryusuke

Foods 12 ( 6 ) 1150 2023年3月

Effect of continuous sweet gustatory stimulation on salivary flow rate over time 査読国際誌

Ranko Yamada, Yuki Tanaka, Hikaru Sugimoto, Naoki Kodama, Ryusuke Yoshida, Shogo Minagi

Archives of Oral Biology 146 105590 - 105590 2023年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Elsevier BV

OBJECTIVE: This study aimed to determine changes in saliva secretion and subjective taste intensity during a sustained period with continuous gustatory stimulation. DESIGN: Twenty-two healthy adults participated in this study. The selected taste solutions were aspartame, sucralose, and acesulfame potassium, which are nonnutritive sweeteners. The concentrations of sucralose1 and acesulfame potassium were set to show the same sweetness intensity as aspartame. Sucralose2 was twice the concentration of sucralose1. The solution was continuously fed into the oral cavity at a flow rate of 0.04 mL / min through a neck-worn precise infusion system. The salivary flow rate (g/min) after 10 min of intraoral water supply from the device was used as the baseline. Salivary flow rate, subjective taste intensity evaluated by the visual analog scale (VAS), and salivary flow rate relative to the baseline were recorded at 10, 30, 60, and 120 min after the start of the test. RESULTS: In the aspartame, sucralose1, and sucralose2 groups, the salivary flow rate increased significantly from 10 min to 120 min after the start of the test when compared to the rate at baseline (p < 0.05). The relative salivary flow rate increased and the VAS value decreased significantly over time and were affected by the time factor (p < 0.001, p = 0.013, respectively) but not by the sweetener-group factor and the interaction effects. CONCLUSIONS: Continuous gustatory stimulation may maintain increased salivary production for a sustained period.

DOI： 10.1016/j.archoralbio.2022.105590

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Phosphatidylinositol‐3 kinase mediates the sweet suppressive effect of leptin in mouse taste cells 査読

Ryusuke Yoshida, Robert F. Margolskee, Yuzo Ninomiya

Journal of Neurochemistry 2021年6月

The sweet taste receptor, glucose transporters, and the ATP-sensitive K+ (KATP) channel: sugar sensing for the regulation of energy homeostasis 査読

Ryusuke Yoshida, Keiko Yasumatsu, Yuzo Ninomiya

Current Opinion in Physiology 20 57 - 63 2021年4月

The sweet taste receptor, glucose transporters, andthe ATP-sensitive K+(KATP) channel: sugar sensingfor the regulation of energy homeostasis 招待査読

20 57 - 63 2021年1月

Orexin A and B in the rat superior salivatory nucleus 査読国際誌

Tadasu Sato, Takehiro Yajima, Masako Fujita, Motoi Kobashi, Hiroyuki Ichikawa, Ryusuke Yoshida, Yoshihiro Mitoh

Autonomic Neuroscience 228 102712 - 102712 2020年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Elsevier BV

Orexin (OX), which regulates sleep and wakefulness and feeding behaviors has 2 isoforms, orexin-A and -B (OXA and OXB). In this study, the distribution of OXA and OXB was examined in the rat superior salivatory nucleus (SSN) using retrograde tracing and immunohistochemical and methods. OXA- and OXB-immunoreactive (-ir) nerve fibers were seen throughout the SSN. These nerve fibers surrounded SSN neurons retrogradely labeled with Fast blue (FB) from the corda-lingual nerve. FB-positive neurons had pericellular OXA- (47.5%) and OXB-ir (49.0%) nerve fibers. Immunohistochemistry for OX receptors also demonstrated the presence of OX1R and OX2R in FB-positive SSN neurons. The majority of FB-positive SSN neurons contained OX1R- (69.7%) or OX2R-immunoreactivity (57.8%). These neurons had small and medium-sized cell bodies. In addition, half of FB-positive SSN neurons which were immunoreactive for OX1R (47.0%) and OX2R (52.2%) had pericellular OXA- and OXB-ir nerve fibers, respectively. Co-expression of OX1R- and OX2R was common in FB-positive SSN neurons. The present study suggests a possibility that OXs regulate the activity of SSN neurons through OX receptors.

DOI： 10.1016/j.autneu.2020.102712

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Sodium‐glucose cotransporter 1 as a sugar taste sensor in mouse tongue 査読国際誌

Keiko Yasumatsu, Tadahiro Ohkuri, Ryusuke Yoshida, Shusuke Iwata, Robert F. Margolskee, Yuzo Ninomiya

Acta Physiologica 230 ( 4 ) e13529 2020年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Wiley

AIM: We investigated potential neuron types that code sugar information and how sodium-glucose cotransporters (SGLTs) and T1Rs are involved. METHODS: Whole-nerve recordings in the chorda tympani (CT) and the glossopharyngeal (GL) nerves and single-fibre recordings in the CT were performed in T1R3-KO and wild-type (WT) mice. Behavioural response measurements were conducted in T1R3-KO mice using phlorizin (Phl), a competitive inhibitor of SGLTs. RESULTS: Results indicated that significant enhancement occurred in responses to sucrose and glucose (Glc) by adding 10 mmol/L NaCl but not in responses to KCl, monopotassium glutamate, citric acid, quinine sulphate, SC45647(SC) or polycose in both CT and GL nerves. These enhancements were abolished by lingual application of Phl. In single-fibre recording, fibres showing maximal response to sucrose could be classified according to responses to SC and Glc with or without 10 mmol/L NaCl in the CT of WT mice, namely, Phl-insensitive type, Phl-sensitive Glc-type and Mixed (Glc and SC responding)-type fibres. In T1R3-KO mice, Phl-insensitive-type fibres disappeared. Results from behavioural experiments showed that the number of licks and amount of intake for Glc with or without 10 mmol/L NaCl were significantly suppressed by Phl. CONCLUSION: We found evidence for the contribution of SGLTs in sugar sensing in taste cells of mouse tongue. Moreover, we found T1R-dependent (Phl-insensitive) type, Glc-type and Mixed (SGLTs and T1Rs)-type fibres. SGLT1 may be involved in the latter two types and may play important roles in the glucose-specific cephalic phase of digestion and palatable food intake.

DOI： 10.1111/apha.13529

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/apha.13529

The Effects of Mutual Interaction of Orexin-A and Glucagon-Like Peptide-1 on Reflex Swallowing Induced by SLN Afferents in Rats 査読

Motoi Kobashi, Yuichi Shimatani, Masako Fujita, Yoshihiro Mitoh, Ryusuke Yoshida, Ryuji Matsuo

International Journal of Molecular Sciences 21 ( 12 ) 4422 - 4422 2020年6月

Effects of bitter receptor antagonists on behavioral lick responses of mice 査読国際誌

Michimasa Masamoto, Yoshihiro Mitoh, Motoi Kobashi, Noriatsu Shigemura, Ryusuke Yoshida

Neuroscience Letters 730 135041 - 135041 2020年6月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Elsevier BV

Bitter taste receptors TAS2Rs detect noxious compounds in the oral cavity. Recent heterologous expression studies reported that some compounds function as antagonists for human TAS2Rs. For examples, amino acid derivatives such as γ-aminobutyric acid (GABA) and Nα,Nα-bis(carboxymethyl)-L-Lysine (BCML) blocked responses to quinine mediated by human TAS2R4. Probenecid inhibited responses to phenylthiocarbamide mediated by human TAS2R38. In this study, we investigated the effects of these human bitter receptor antagonists on behavioral lick responses of mice to elucidate whether these compounds also function as bitter taste blockers. In short-term (10 s) lick tests, concentration-dependent lick responses to bitter compounds (quinine-HCl, denatonium and phenylthiourea) were not affected by the addition of GABA or BCML. Probenecid reduced aversive lick responses to denatonium and phenylthiourea but not to quinine-HCl. In addition, taste cell responses to phenylthiourea were inhibited by probenecid. These results suggest some bitter antagonists of human TAS2Rs can work for bitter sense of mouse.

DOI： 10.1016/j.neulet.2020.135041

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