| 重村 憲徳（しげむら のりあつ） | データ更新日：2023.11.22 |
教授 ／
歯学研究院
歯学部門
口腔常態制御学講座
| 1. | Sanematsu K, Yamamoto M, Nagasato Y, Kawabata Y, Watanabe Y, Iwata S, Takai S, Toko K, Matsui T, Wada N, Shigemura N., Prediction of dynamic allostery for the transmembrane domain of the sweet taste receptor subunit, TAS1R3, Commun Biol., 10.1038/s42003-023-04705-5., 6(1), 340, 2023.04. |
| 2. | Matsuyama K, Takai S, Shigemura N, Nakatomi M, Kawamoto T, Kataoka S, Toyono T, Seta Y., Ascl1-expressing cell differentiation in initially developed taste buds and taste organoids. , Cell Tissue Res., 10.1007/s00441-023-03756-8., 2023.02. |
| 3. | Oike A, Iwata S, Hirayama A, Ono Y, Nagasato Y, Kawabata Y, Takai S, Sanematsu K, Wada N, Shigemura N., Bisphosphonate affects the behavioral responses to HCl by disrupting farnesyl diphosphate synthase in mouse taste bud and tongue epithelial cells , Sci Rep., 10.1038/s41598-022-25755-5, 12(1), 21246, 2022.12. |
| 4. | Yuna Lee, Akihiro Nakano, Saya Nakamura, Kenta Sakai, Mitsuru Tanaka, Keisuke Sanematsu, Noriatsu Shigemura and Toshiro Matsui, In vitro and in silico characterization of adiponectin-receptor agonist dipeptides., npj Science of Food, 5(1), 29, 2021.10. |
| 5. | Serrano J, Seflova J, Park J, Pribadi M, Sanematsu K, Shigemura N, Serna V, Yi F, Mari A, Procko E, Pratley RE, Robia SL, Kyriazis GA., The Ile191Val is a partial loss-of-function variant of the TAS1R2 sweet-taste receptor and is associated with reduced glucose excursions in humans. , Mol Metab. , 10.1016/j.molmet.2021.101339. , 54, 101339., 2021.09, [URL]. |
| 6. | Yamada Y, Takai S, Watanabe Y, Osaki A, Kawabata Y, Oike A, Hirayama A, Iwata S, Sanematsu K, Tabata S, Shigemura N., Gene expression profiling of α-gustducin-expressing taste cells in mouse fungiform and circumvallate papillae, Biochem Biophys Res Commun., 10.1016/j.bbrc.2021.04.022, 557, 206-212, 2021.04, [URL]. |
| 7. | Fumie Hirose, Shingo Takai, Ichiro Takahashi, Noriatsu Shigemura, Expression of protocadherin-20 in mouse taste buds, Scientific reports, 10.1038/s41598-020-58991-8, 10, 1, 2020.12, [URL], 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.. |
| 8. | Osaki A, Sanematsu K, Yamazoe J, Hirose F, Watanabe Y, Kawabata Y, Oike A, Hirayama A, Yamada Y, Iwata S, Takai S, Wada N, Shigemura N, Drinking Ice-cold Water Reduces the Severity of Anticancer Drug-induced Taste Dysfunction in Mice, Int J Mol Sci., 10.3390/ijms21238958, 21, (23), 8958, 2020.11, [URL], 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.. |
| 9. | Michimasa Masamoto, Yoshihiro Mitoh, Motoi Kobashi, Noriatsu Shigemura, Ryusuke Yoshida, Effects of bitter receptor antagonists on behavioral lick responses of mice, Neuroscience Letters, 10.1016/j.neulet.2020.135041, 730, 135041-135041, 2020.06, © 2020 Elsevier B.V. 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.. |
| 10. | Takai S, Shigemura N., Insulin Function in Peripheral Taste Organ Homeostasis, Curr Oral Health Rep., 10.1007/s40496-020-00266-2, 730, 2020.05. |
| 11. | Shigemura N, Takai S, Hirose F, Yoshida R, Sanematsu K, Ninomiya Y., Expression of Renin-Angiotensin System Components in the Taste Organ of Mice, Nutrients., 10.3390/nu11092251, 11, 9, 11(9). pii: E2251, 2019.09. |
| 12. | Jihye Park, Balaji Selvam, Keisuke Sanematsu, Noriatsu Shigemura, Diwakar Shukla, Erik Procko, Structural architecture of a dimeric class C GPCR based on co-trafficking of sweet taste receptor subunits, Journal of Biological Chemistry, 10.1074/jbc.RA118.006173, 294, 13, 4759-4774, 2019.03, [URL], 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.. |
| 13. | Shingo Takai, Yu Watanabe, Keisuke Sanematsu, Ryusuke Yoshida, Robert F. Margolskee, Peihua Jiang, Ikiru Atsuta, Kiyoshi Koyano, Yuzo Ninomiya, Noriatsu Shigemura, Effects of insulin signaling on mouse taste cell proliferation, PloS one, 10.1371/journal.pone.0225190, 14, 11, 2019.01, [URL], 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.. |
| 14. | Keisuke Sanematsu, Yuki Nakamura, Masatoshi Nomura, Noriatsu Shigemura, Yuzo Ninomiya, Diurnal variation of sweet taste recognition thresholds is absent in overweight and obese humans, Nutrients, 10.3390/nu10030297, 10, 3, 2018.03, © 2018 by the authors. Licensee MDPI, Basel, Switzerland. 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.. |
| 15. | Ryusuke Yoshida, Shingo Takai, Keisuke Sanematsu, Robert F. Margolskee, Noriatsu Shigemura, Yuzo Ninomiya, Bitter Taste Responses of Gustducin-positive Taste Cells in Mouse Fungiform and Circumvallate Papillae, Neuroscience, 10.1016/j.neuroscience.2017.10.047, 369, 29-39, 2018.01, © 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.. |
| 16. | Ryusuke Yoshida, Misa Shin, Keiko Yasumatsu, Shingo Takai, Mayuko Inoue, Noriatsu Shigemura, Soichi Takiguchi, Seiji Nakamura, Yuzo Ninomiya, The role of cholecystokinin in peripheral taste signaling in mice, Frontiers in Physiology, 10.3389/fphys.2017.00866, 8, OCT, 866-866, 2017.10, © 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.. |
| 17. | Keisuke Sanematsu, Noriatsu Shigemura, Yuzo Ninomiya, Binding properties between human sweet receptor and sweet-inhibitor, gymnemic acids, journal of oral biosciences, 10.1016/j.job.2017.05.004, 59, 3, 127-130, 2017.08, [URL], Background Gymnemic acids, triterpene glycosides, are known to act as human-specific sweet inhibitors. The long-lasting effect of gymnemic acids is diminished by γ-cyclodextrin. Here, we focus on the molecular mechanisms underlying the interaction between gymnemic acids and sweet taste receptor and/or γ-cyclodextrin by a sweet taste receptor assay in transiently transfected HEK293 cells. Highlight Application of gymnemic acids inhibited intracellular calcium responses to sweet compounds in HEK293 cells expressing human TAS1R2+TAS1R3 but not in those expressing the mouse sweet receptor Tas1r2+Tas1r3 after application of gymnemic acids. The effect of gymnemic acids was reduced after rinsing cells with γ-cyclodextrin. Based on species-specific sensitivities to gymnemic acids, we showed that the transmembrane domain of hTAS1R3 is involved in the sensitivity to gymnemic acids. Point mutation analysis in the transmembrane domain of hTAS1R3 revealed that gymnemic acids shared the same binding pocket with another sweet inhibitor, lactisole. Sensitivity to sweet compounds was also reduced by mixtures of glucuronic acid, a common gymnemic acid. In our molecular models, gymnemic acids interacted with a binding site formed in the transmembrane domain of hTAS1R3. Conclusion Gymnemic acids inhibit sweet responses in humans through an interaction between the glucuronosyl group of gymnemic acids and the transmembrane domain of hTAS1R3. Our molecular model provides a foundation for the development of taste modifiers.. |
| 18. | Masafumi Jyotaki, Keisuke Sanematsu, Noriatsu Shigemura, Ryusuke Yoshida, Yuzo Ninomiya, Leptin suppresses sweet taste responses of enteroendocrine STC-1 cells, Neuroscience, 10.1016/j.neuroscience.2016.06.036, 332, 76-87, 2016.09, © 2016 IBRO 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 Ca2+ responses of STC-1 cells to various taste compounds. Ca2+ 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 ⩾1 ng/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.. |
| 19. | Sunil K. Sukumarana, Karen K. Yeea, Shusuke Iwatab, Ramana Kothaa, Roberto Quezada-Calvillo, Buford L. Nichols, Sankar Mohan, B. Mario Pinto, Noriatsu Shigemura, Yuzo Ninomiya, Robert F. Margolskee, Taste cell-expressed α-glucosidase enzymes contribute to gustatory responses to disaccharides, Proceedings of the National Academy of Sciences of the United States of America, 10.1073/pnas.1520843113, 113, 21, 6035-6040, 2016.05, The primary sweet sensor in mammalian taste cells for sugars and noncaloric sweeteners is the heteromeric combination of type 1 taste receptors 2 and 3 (T1R2+T1R3, encoded by Tas1r2 and Tas1r3 genes). However, in the absence of T1R2+T1R3 (e.g., in Tas1r3 KO mice), animals still respond to sugars, arguing for the presence of T1Rindependent detection mechanism(s). Our previous findings that several glucose transporters (GLUTs), sodium glucose cotransporter 1 (SGLT1), and the ATP-gated K+ (KATP ) metabolic sensor are preferentially expressed in the same taste cells with T1R3 provides a potential explanation for the T1R-independent detection of sugars: sweet-responsive taste cells that respond to sugars and sweeteners may contain a T1R-dependent (T1R2+T1R3) sweet-sensing pathway for detecting sugars and noncaloric sweeteners, as well as a T1Rindependent (GLUTs, SGLT1, KATP ) pathway for detecting monosaccharides. However, the T1R-independent pathway would not explain responses to disaccharide and oligomeric sugars, such as sucrose, maltose, and maltotriose, which are not substrates for GLUTs or SGLT1. Using RT-PCR, quantitative PCR, in situ hybridization, and immunohistochemistry, we found that taste cells express multiple α-glycosidases (e.g., amylase and neutral α glucosidase C) and so-called intestinal "brush border" disaccharide-hydrolyzing enzymes (e.g., maltase-glucoamylase and sucrase-isomaltase). Treating the tongue with inhibitors of disaccharidases specifically decreased gustatory nerve responses to disaccharides, but not to monosaccharides or noncaloric sweeteners, indicating that lingual disaccharidases are functional. These taste cell-expressed enzymes may locally break down dietary disaccharides and starch hydrolysis products into monosaccharides that could serve as substrates for the T1R-independent sugar sensing pathways.. |
| 20. | Keisuke Sanematsu, Masayuki Kitagawa, Ryusuke Yoshida, Satoru Nirasawa, Noriatsu Shigemura, Yuzo Ninomiya, Intracellular acidification is required for full activation of the sweet taste receptor by miraculin, Scientific Reports, 10.1038/srep22807, 6, 22807-22807, 2016.03, 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.. |
| 21. | Noriatsu Shigemura, Yuzo Ninomiya, Recent Advances in Molecular Mechanisms of Taste Signaling and Modifying., Int Rev Cell Mol Biol., 323, 71-106, 2016.02. |
| 22. | Shingo Takai, Ryusuke Yoshida, Noriatsu Shigemura, Yuzo Ninomiya, Peptide Signaling in Taste Transduction, Chemosensory Transduction: The Detection of Odors, Tastes, and Other Chemostimuli, 10.1016/B978-0-12-801694-7.00017-2, 299-317, 2016.02, © 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.. |
| 23. | Shingo Takai, Ryusuke Yoshida, Keiko Yasumatsu, Noriatsu Shigemura, Yuzo Ninomiya, The function of glucagon-like peptide-1 in the mouse peripheral taste system, Journal of Oral Biosciences, 10.1016/j.job.2015.09.002, 58, 1, 10-15, 2016.02, © 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.. |
| 24. | Ryusuke Yoshida, Kenshi Noguchi, Noriatsu Shigemura, Masafumi Jyotaki, Ichiro Takahashi, Robert F. Margolskee, Yuzo Ninomiya, Leptin suppresses mouse taste cell responses to sweet compounds, Diabetes, 10.2337/db14-1462, 64, 11, 3751-3762, 2015.11, © 2015 by the American Diabetes Association. Leptin is known to selectively suppress neural and behavioral responses to sweet-tasting compounds. However, themolecular basis for the effect of leptin on sweet taste is not known. Here, we report that leptin suppresses sweet taste via leptin receptors (Ob-Rb) and KATP channels expressed selectively in sweet-sensitive taste cells. Ob-Rb was more often expressed in taste cells that expressed T1R3 (a sweet receptor component) than in those that expressed glutamate-aspartate transporter (a marker for Type I taste cells) or GAD67 (a marker for Type III taste cells). Systemically administered leptin suppressed taste cell responses to sweet but not to bitter or sour compounds. This effect was blocked by a leptin antagonist and was absent in leptin receptor-deficient db/db mice and mice with diet-induced obesity. Blocking the KATP channel subunit sulfonylurea receptor 1, which was frequently coexpressed with Ob-Rb in T1R3-expressing taste cells, eliminated the effect of leptin on sweet taste. In contrast, activating the KATP channel with diazoxide mimicked the sweet-suppressing effect of leptin. These results indicate that leptin acts via Ob-Rb and KATP channels that are present in T1R3-expressing taste cells to selectively suppress their responses to sweet compounds.. |
| 25. | Noriatsu Shigemura, Modulation of Taste Responsiveness by Angiotensin II., Food Science and Technology Research, 21 , 6, 757-764, 2015.06. |
| 26. | Shingo Takai, Keiko Yasumatsu, Mayuko Inoue, Shusuke Iwata, Ryusuke Yoshida, Noriatsu Shigemura, Yuchio Yanagawa, Daniel J. Drucker, Robert F. Margolskee, Yuzo Ninomiya, Glucagon-like peptide-1 is specifically involved in sweet taste transmission, FASEB Journal, 10.1096/fj.14-265355, 29, 6, 2268-2280, 2015.06, © 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.. |
| 27. | Mayu Niki, Masafumi Jyotaki, Ryusuke Yoshida, Keiko Yasumatsu, Noriatsu Shigemura, Nicholas V. DiPatrizio, Daniele Piomelli, Yuzo Ninomiya, Modulation of sweet taste sensitivities by endogenous leptin and endocannabinoids in mice, Journal of Physiology, 10.1113/JP270295, 593, 11, 2527-2545, 2015.06, © 2015 The Physiological Society. Leptin is an anorexigenic mediator that reduces food intake by acting on hypothalamic receptor Ob-Rb. In contrast, endocannabinoids are orexigenic mediators that act via cannabinoid CB1 receptors in hypothalamus, limbic forebrain, and brainstem. In the peripheral taste system, leptin administration selectively inhibits behavioural, taste nerve and taste cell responses to sweet compounds. Opposing the action of leptin, endocannabinoids enhance sweet taste responses. However, potential roles of endogenous leptin and endocannabinoids in sweet taste remain unclear. Here, we used pharmacological antagonists (Ob-Rb: L39A/D40A/F41A (LA), CB1: AM251) and examined the effects of their blocking activation of endogenous leptin and endocannabinoid signalling on taste responses in lean control, leptin receptor deficient db/db, and diet-induced obese (DIO) mice. Lean mice exhibited significant increases in chorda tympani (CT) nerve responses to sweet compounds after LA administration, while they showed no significant changes in CT responses after AM251. In contrast, db/db mice showed clear suppression of CT responses to sweet compounds after AM251, increased endocannabinoid (2-arachidonoyl-sn-glycerol (2-AG)) levels in the taste organ, and enhanced expression of a biosynthesizing enzyme (diacylglycerol lipase α (DAGLα)) of 2-AG in taste cells. In DIO mice, the LA effect was gradually decreased and the AM251 effect was increased during the course of obesity. Taken together, our results suggest that circulating leptin, but not local endocannabinoids, may be a dominant modulator for sweet taste in lean mice; however, endocannabinoids may become more effective modulators of sweet taste under conditions of deficient leptin signalling, possibly due to increased production of endocannabinoids in taste tissue.. |
| 28. | Noriatsu Shigemura, Angiotensin II and taste sensitivity., Japanese Dental Science Review, 51, 2, 51-8, 2015.05. |
| 29. | Keisuke Sanematsu, Ryusuke Yoshida, Noriatsu Shigemura, Yuzo Ninomiya, Structure, function, and signaling of taste G-protein-coupled receptors., Curr Pharm Biotechnol., 15, 10, 951-61, 2014.10. |
| 30. | Keisuke Sanematsu, Yuko Kusakabe, Noriatsu Shigemura, Takatsugu Hirokawa, Seiji Nakamura, Toshiaki Imoto, Yuzo Ninomiya, Molecular mechanisms for sweet-suppressing effect of gymnemic acids, Journal of Biological Chemistry, 10.1074/jbc.M114.560409, 289, 37, 25711-25720, 2014.09, © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Gymnemic acids are triterpene glycosides that selectively suppress taste responses to various sweet substances in humans but not in mice. This sweet-suppressing effect of gymnemic acids is diminished by rinsing the tongue with γ-cyclodextrin (γ-CD). However, little is known about the molecular mechanisms underlying the sweet-suppressing effect of gymnemic acids and the interaction between gymnemic acids versus sweet taste receptor and/or γ-CD. To investigate whether gymnemic acids directly interact with human (h) sweet receptor hT1R2 + hT1R3, we used the sweet receptor T1R2 + T1R3 assay in transiently transfected HEK293 cells. Similar to previous studies in humans and mice, gymnemic acids (100 μg/ml) inhibited the [Ca2+]iresponses to sweet compounds in HEK293 cells heterologously expressing hT1R2 + hT1R3 but not in those expressing the mouse (m) sweet receptor mT1R2 + mT1R3. The effect of gymnemic acids rapidly disappeared after rinsing the HEK293 cells with γ-CD. Using mixed species pairings of human and mouse sweet receptor subunits and chimeras, we determined that the transmembrane domain of hT1R3 was mainly required for the sweet-suppressing effect of gymnemic acids. Directed mutagenesis in the transmembrane domain of hT1R3 revealed that the interaction site for gymnemic acids shared the amino acid residues that determined the sensitivity to another sweet antagonist, lactisole. Glucuronic acid, which is the common structure of gymnemic acids, also reduced sensitivity to sweet compounds. In our models, gymnemic acids were predicted to dock to a binding pocket within the transmembrane domain of hT1R3.. |
| 31. | Noriatsu Shigemura, Shusuke Iwata, Keiko Yasumatsu, Tadahiro Ohkuri, Nao Horio, Keisuke Sanematsu, Ryusuke Yoshida, Robert F Margolskee, Yuzo Ninomiya, Angiotensin II modulates salty and sweet taste sensitivities., J Neurosci., 33, 15, 6267-6277, 2013.04, アンジオテンシンIIは、視床下部、副腎や血管などに発現するAT1受容体を介して、血圧や体内Na+濃度を調節する鍵ホルモンとして知られている。我々は、このアンジオテンシンIIが末梢の味覚器にも働き、塩味感受性を低下させ NaCl溶液の摂取量を増加させること、さらに甘味感受性を増強することで糖分摂取にも影響することを明らかにした。この“味覚を介したNa+/糖ホメオスタシス維持機構”のさらなる解明は、高血圧や肥満・糖尿病などの生活習慣病に対する新たな予防・治療法の開発”に繋がることが期待される。. |
| 32. | Ryusuke Yoshida, Mayu Niki, Masafumi Jyotaki, Keisuke Sanematsu, Noriatsu Shigemura, Yuzo Ninomiya, Modulation of sweet responses of taste receptor cells, Seminars in Cell and Developmental Biology, 10.1016/j.semcdb.2012.08.004, 24, 3, 226-231, 2013.03, Taste receptor cells play a major role in detection of chemical compounds in the oral cavity. Information derived from taste receptor cells, such as sweet, bitter, salty, sour and umami is important for evaluating the quality of food components. Among five basic taste qualities, sweet taste is very attractive for animals and influences food intake. Recent studies have demonstrated that sweet taste sensitivity in taste receptor cells would be affected by leptin and endocannabinoids. Leptin is an anorexigenic mediator that reduces food intake by acting on leptin receptor Ob-Rb in the hypothalamus. Endocannabinoids such as anandamide [N-arachidonoylethanolamine (AEA)] and 2-arachidonoyl glycerol (2-AG) are known as orexigenic mediators that act via cannabinoid receptor 1 (CB1) in the hypothalamus and limbic forebrain to induce appetite and stimulate food intake. At the peripheral gustatory organs, leptin selectively suppresses and endocannabinoids selectively enhance sweet taste sensitivity via Ob-Rb and CB1 expressed in sweet sensitive taste cells. Thus leptin and endocannabinoids not only regulate food intake via central nervous systems but also modulate palatability of foods by altering peripheral sweet taste responses. Such reciprocal modulation of leptin and endocannabinoids on peripheral sweet sensitivity may play an important role in regulating energy homeostasis. © 2012 Elsevier Ltd.. |
| 33. | Cristina Cartoni, Keiko Yasumatsu, Tadahiro Ohkuri, Noriatsu Shigemura, Ryusuke Yoshida, Nicolas Godinot, Johannes Le Coutre, Yuzo Ninomiya, Sami Damak, Taste preference for fatty acids is mediated by GPR40 and GPR120, Journal of Neuroscience, 10.1523/JNEUROSCI.0496-10.2010, 30, 25, 8376-8382, 2010.06, The oral perception of fat has traditionally been considered to rely mainly on texture and olfaction, but recent findings suggest that taste may also play a role in the detection of long chain fatty acids. The two G-protein coupled receptors GPR40 (Ffar1) and GPR120 are activated by medium and long chain fatty acids. Here we show that GPR120 and GPR40 are expressed in the taste buds, mainly in type II and type I cells, respectively. Compared with wild-type mice, male and female GPR120 knock-out and GPR40 knock-out mice show a diminished preference for linoleic acid and oleic acid, and diminished taste nerve responses to several fatty acids. These results show that GPR40 and GPR120 mediate the taste of fatty acids. Copyright © 2010 the authors.. |
| 34. | Jyotaki M, Shigemura N, Ninomiya Y., Modulation of sweet taste sensitivity by orexigenic and anorexigenic factors., Endocr J., 2010.04. |
| 35. | Yoshida R, Ohkuri T, Jyotaki M, Yasuo T, Horio N, Yasumatsu K, Sanematsu K, Shigemura N, Yamamoto T, Margolskee RF, Ninomiya Y., Endocannabinoids selectively enhance sweet taste., Proc Natl Acad Sci U S A., 107(2):935-9., 2010.01. |
| 36. | Horio N, Jyotaki M, Yoshida R, Sanematsu K, Shigemura N, Ninomiya Y., New frontiers in gut nutrient sensor research: nutrient sensors in the gastrointestinal tract: modulation of sweet taste sensitivity by leptin., J Pharmacol Sci., 112(1):8-12., 2010.01. |
| 37. | 安尾敏明、吉田竜介、堀尾奈央、重村憲徳、二ノ宮裕三., マウス味細胞におけるGABAの機能解析., 日本味と匂学会誌, 16(3):323-326, 2009.12. |
| 38. | 實松敬介、重村憲徳、上瀧将史、中村誠司、井元敏明、二ノ宮裕三., ヒトT1R2/T1R3に対するギムネマ酸の相互作用部位の同定., 日本味と匂学会誌, 16(3):287-290, 2009.12. |
| 39. | Keiko Yasumatsu, Tadahiro Ohkuri, Keisuke Sanematsu, Noriatsu Shigemura, Hideo Katsukawa, Noritaka Sako, Yuzo Ninomiya, Genetically-increased taste cell population with Gα-gustducin-coupled sweet receptors is associated with increase of gurmarin-sensitive taste nerve fibers in mice, BMC Neuroscience, 10.1186/1471-2202-10-152, 10, 152-152, 2009.12, Background: The peptide gurmarin is a selective sweet response inhibitor for rodents. In mice, gurmarin sensitivity differs among strains with gurmarin-sensitive C57BL and gurmarin-poorly-sensitive BALB strains. In C57BL mice, sweet-responsive fibers of the chorda tympani (CT) nerve can be divided into two distinct populations, gurmarin-sensitive (GS) and gurmarin-insensitive (GI) types, suggesting the existence of two distinct reception pathways for sweet taste responses. By using the dpa congenic strain (dpa CG) whose genetic background is identical to BALB except that the gene(s) controlling gurmarin sensitivity are derived from C57BL, we previously found that genetically-elevated gurmarin sensitivity in dpa CG mice, confirmed by using behavioral response and whole CT nerve response analyses, was linked to a greater taste cell population co-expressing sweet taste receptors and a Gα protein, Gα-gustducin. However, the formation of neural pathways from the increased taste cell population to nerve fibers has not yet been examined.Results: Here, we investigated whether the increased taste cell population with Gα-gustducin-coupled sweet receptors would be associated with selective increment of GS fiber population or nonselective shift of gurmarin sensitivities of overall sweet-responsive fibers by examining the classification of GS and GI fiber types in dpa CG and BALB mice. The results indicated that dpa CG, like C57BL, possess two distinct populations of GS and GI types of sweet-responsive fibers with almost identical sizes (dpa CG: 13 GS and 16 GI fibers; C57BL: 16 GS and 14 GI fibers). In contrast, BALB has only 3 GS fibers but 18 GI fibers. These data indicate a marked increase of the GS population in dpa CG.Conclusion: These results suggest that the increased cell population expressing T1r2/T1r3/Gα-gustducin in dpa CG mice may be associated with an increase of their matched GS type fibers, and may form the distinct GS sweet reception pathway in mice. Gα-gustducin may be involved in the GS sweet reception pathway and may be a key molecule for links between sweet taste receptors and cell type-specific-innervation by their matched fiber class. © 2009 Yasumatsu et al; licensee BioMed Central Ltd.. |
| 40. | Shigemura N, Shirosaki S, Ohkuri T, Sanematsu K, Islam AA, Ogiwara Y, Kawai M, Yoshida R, Ninomiya Y., Variation in umami perception and in candidate genes for the umami receptor in mice and humans. , Am J Clin Nutr. , 90(3):764S-769S., 2009.09. |
| 41. | Ryusuke Yoshida, Aya Miyauchi, Toshiaki Yasuo, Masafumi Jyotaki, Yoshihiro Murata, Keiko Yasumatsu, Noriatsu Shigemura, Yuchio Yanagawa, Kunihiko Obata, Hiroshi Ueno, Robert F. Margolskee, Yuzo Ninomiya, Discrimination of taste qualities among mouse fungiform taste bud cells, Journal of Physiology, 10.1113/jphysiol.2009.175075, 587, 18, 4425-4439, 2009.09, Multiple lines of evidence from molecular studies indicate that individual taste qualities are encoded by distinct taste receptor cells. In contrast, many physiological studies have found that a significant proportion of taste cells respond to multiple taste qualities. To reconcile this apparent discrepancy and to identify taste cells that underlie each taste quality, we investigated taste responses of individual mouse fungiform taste cells that express gustducin or GAD67, markers for specific types of taste cells. Type II taste cells respond to sweet, bitter or umami tastants, express taste receptors, gustducin and other transduction components. Type III cells possess putative sour taste receptors, and have well elaborated conventional synapses. Consistent with these findings we found that gustducin-expressing Type II taste cells responded best to sweet (25/49), bitter (20/49) or umami (4/49) stimuli, while all GAD67 (Type III) taste cells examined (44/44) responded to sour stimuli and a portion of them showed multiple taste sensitivities, suggesting discrimination of each taste quality among taste bud cells. These results were largely consistent with those previously reported with circumvallate papillae taste cells. Bitter-best taste cells responded to multiple bitter compounds such as quinine, denatonium and cyclohexamide. Three sour compounds, HCl, acetic acid and citric acid, elicited responses in sour-best taste cells. These results suggest that taste cells may be capable of recognizing multiple taste compounds that elicit similar taste sensation. We did not find any NaCl-best cells among the gustducin and GAD67 taste cells, raising the possibility that salt sensitive taste cells comprise a different population. © 2009 The Authors. Journal compilation © 2009 The Physiological Society.. |
| 42. | Shigemura N, Shirosaki S, Sanematsu K, Yoshida R, Ninomiya Y., Genetic and molecular basis of individual differences in human umami taste perception., PLoS One., 4(8):e6717., 2009.08. |
| 43. | Keisuke Sanematsu, Nao Horio, Yoshihiro Murata, Ryusuke Yoshida, Tadahiro Ohkuri, Noriatsu Shigemura, Yuzo Ninomiya, Modulation and transmission of sweet taste information for energy homeostasis, Annals of the New York Academy of Sciences, 10.1111/j.1749-6632.2009.03893.x, 1170, 102-106, 2009.07, Perception of sweet taste is important for animals to detect external energy source of calories. In mice, sweet-sensitive cells possess a leptin receptor. Increase of plasma leptin with increasing internal energy storage in the adipose tissue suppresses sweet taste responses via this receptor. Data from our recent studies indicate that leptin may also modulate sweet taste sensation in humans with a diurnal variation in sweet sensitivity. This leptin modulation of sweet taste information to the brain may influence individuals' preference and ingestive behavior, thereby playing important roles in regulation of energy homeostasis. © 2009 New York Academy of Sciences.. |
| 44. | Ryusuke Yoshida, Keiko Yasumatsu, Shinya Shirosaki, Masashi Jyotaki, Nao Horio, Yoshihiro Murata, Noriatsu Shigemura, Kiyohito Nakashima, Yuzo Ninomiya, Multiple receptor systems for umami taste in mice, Annals of the New York Academy of Sciences, 10.1111/j.1749-6632.2009.03902.x, 1170, 51-54, 2009.07, Recent molecular studies proposed that the T1r1T1r3 heterodimer, mGluR1 and mGluR4 might function as umami taste receptors in mice. However, the roles of each of these receptors in umami taste are not yet clear. In this paper, we summarize recent data for T1r3, mGluR1, and mGluR4 as umami taste receptors and discuss receptor systems responsible for umami detection in mice. © 2009 New York Academy of Sciences.. |
| 45. | Nakagawa Y, Nagasawa M, Yamada S, Hara A, Mogami H, Nikolaev VO, Lohse MJ, Shigemura N, Ninomiya Y, Kojima I., Sweet taste receptor expressed in pancreatic beta-cells activates the calcium and cyclic AMP signaling systems and stimulates insulin secretion., PLoS One., 4(4):e5106, 2009.04. |
| 46. | Yoshida R, Horio N, Murata Y, Yasumatsu K, Shigemura N, Ninomiya Y., NaCl responsive taste cells in the mouse fungiform taste buds., Neuroscience., 159(2):795-803., 2009.03. |
| 47. | 城崎慎也、川東由利子、中島清人、重村憲徳、安松啓子、吉田竜介、Robert F. Margolskee、二ノ宮裕三., mGluRアンタゴニスト混合うま味溶液に対するT1R3-KOおよびC57BL/６マウスの行動学的解析., 日本味と匂学会誌., 15:293-6., 2008.12. |
| 48. | 實松敬介、重村憲徳、中村誠司、井元敏明、二ノ宮裕三., トリテルペン配糖体とヒト甘味受容体hT1R2/hT1R3の相互作用., 日本味と匂学会誌., 15:297-300., 2008.12. |
| 49. | 中島清人、勝川秀夫、城崎慎也、重村憲徳、二ノ宮裕三., グルタミン酸受容体アンタゴニスト添加うま味物質で嫌悪条件付けそたマウスの各種味物質に対する般化., 日本味と匂学会誌., 15:653-6., 2008.12. |
| 50. | Nakamura Y, Sanematsu K, Ohta R, Shirosaki S, Koyano K, Nonaka K, Shigemura N, Ninomiya Y., Diurnal variation of human sweet taste recognition thresholds is correlated with plasma leptin levels., Diabetes. , 57(10):2661-5., 2008.10. |
| 51. | Shigemura, N., Nakao, K., Yasuo, T., Murata, Y., Yasumatsu, K., Nakashima, A., Katsukawa, H., Sako, N., Ninomiya, Y. , Gurmarin sensitivity of sweet taste responses is associated with co-expression patterns of T1r2, T1r3, and gustducin. , Biochem. Biophys. Res. Commun., 367, 356-363 , 2008.03. |
| 52. | Shigemura, N., Ohkuri, T., Sadamitsu, C., Yasumatsu, K., Yoshida, R., Beauchamp, G.K., Bachmanov, A.A., Ninomiya, Y. , Amiloride-sensitive NaCl taste responses are associated with genetic variation of ENaC α subunit in mice., Am. J. Physiol. Regul Integr. Comp. Physiol., 294, R66-R75 , 2008.01. |
| 53. | 實松敬介、重村憲徳、二ノ宮裕三, 甘味およびうま味受容体応答特性, 日本味と匂学会誌, 14, 375-378, 2007.12. |
| 54. | 城崎慎也、川東由利子、重村憲徳、安松啓子、吉田竜介、Margolskee, R.F.、二ノ宮裕三, T1R3-KOマウスにおけるうま味物質に対する条件付け味覚嫌悪学習, 日本味と匂学会誌, 14, 379-382 , 2007.12. |
| 55. | Keiko Yasumatsu, Yoko Kusuhara, Noriatsu Shigemura, Yuzo Ninomiya, Recovery of two independent sweet taste systems during regeneration of the mouse chorda tympani nerve after nerve crush, European Journal of Neuroscience, 10.1111/j.1460-9568.2007.05761.x, 26, 6, 1521-1529, 2007.09, In rodents, section of the taste nerve results in degeneration of the taste buds. Following regeneration of the cut taste nerve, however, the taste buds reappear. This phenomenon can be used to study the functional reformation of the peripheral neural system responsible for sweet taste. In this study we examined the recovery of sweet responses by the chorda tympani (CT) nerve after nerve crush as well as inhibition of these responses by gurmarin (Gur), a sweet response inhibitor. After about 2 weeks of CT nerve regeneration, no significant response to any taste stimuli could be observed. At 3 weeks, responses to sweet stimuli reappeared but were not significantly inhibited by Gur. At 4 weeks, Gur inhibition of sweet responses reached statistically significant levels. Thus, the Gur-sensitive (GS) component of the sweet response reappeared about 1 week later than the Gur-insensitive (GI) component. Moreover, single CT fibers responsive to sucrose could be classified into distinct GS and GI groups at 4 weeks. After 5 weeks or more, responses to sweet compounds before and after treatment with Gur became indistinguishable from responses in the intact group. During regeneration, the GS and GI components of the sucrose response could be distinguished based on their concentration-dependent responses to sucrose. These results suggest that mice have two different sweet-reception systems, distinguishable by their sensitivity to Gur (the GS and GI systems). These two sweet-reception systems may be reconstituted independently during regeneration of the mouse CT nerve. © The Authors (2007).. |
| 56. | 重村憲徳、安松啓子、吉田竜介、二ノ宮裕三, 甘味感受性に影響する温度依存的なTrpm5の働き , 低温生物工学会誌, 53, 53-55 , 2007.08. |
| 57. | 吉田竜介、大栗弾宏、安松啓子、重村憲徳、二ノ宮裕三, マウス茸状乳頭味細胞のNaCl応答：アミロライド感受性細胞と非感受性細胞, 日本味と匂学会誌, 13巻、3号、351-354, 2006.12. |
| 58. | 安松啓子、吉田竜介、重村憲徳、Sami Damak、Robert F Margolskee、二ノ宮裕三, T1R3-KO、TRPM5-KOマウス鼓索神経におけるうま味応答神経線維の解析, 日本味と匂学会誌, 13巻、3号、335-338, 2006.12. |
| 59. | 大栗弾宏、安松啓子、吉田竜介、重村憲徳、二ノ宮裕三, C57BL/6NとBALB/cマウスの鼓索神経甘味応答の刺激温度による変化, 日本味と匂学会誌, 13巻、3号、339-342, 2006.12. |
| 60. | 實松敬介、安松啓子、吉田竜介、重村憲徳、二ノ宮裕三, Tas1r3遺伝子型とグルマリン感受性の相関, 日本味と匂学会誌, 13巻、3号、343-346, 2006.12. |
| 61. | 城崎慎也、重村憲徳、吉田竜介、安松啓子、Robert F Margolskee、二ノ宮裕三, T1R3-KOマウスの甘味物質に対する行動応答の解析, 日本味と匂学会誌, 13巻、3号、347-350, 2006.12. |
| 62. | 重村憲徳、大栗弾宏、貞光千春、安松啓子、吉田竜介、AA Bachmanov、GK Beauchamp、二ノ宮裕三, ENaC遺伝子多型性とアミロライド感受性との相関, 日本味と匂学会誌, 13巻、3号、355-358, 2006.12. |
| 63. | Ryusuke Yoshida, Noriatsu Shigemura, Keisuke Sanematsu, Keiko Yasumatsu, Satoru Ishizuka, Yuzo Ninomiya, Taste responsiveness of fungiform taste cells with action potentials, Journal of Neurophysiology, 10.1152/jn.00409.2006, 96, 6, 3088-3095, 2006.12, It is known that a subset of taste cells generate action potentials in response to taste stimuli. However, responsiveness of these cells to particular tastants remains unknown. In the present study, by using a newly developed extracellular recording technique, we recorded action potentials from the basolateral membrane of single receptor cells in response to taste stimuli applied apically to taste buds isolated from mouse fungiform papillae. By this method, we examined taste-cell responses to stimuli representing the four basic taste qualities (NaCl, Na saccharin, HCl, and quinine-HCl). Of 72 cells responding to taste stimuli, 48 (67%) responded to one, 22 (30%) to two, and 2 (3%) to three of four taste stimuli. The entropy value presenting the breadth of responsiveness was 0.158 ± 0.234 (mean ± SD), which was close to that for the nerve fibers (0.183 ± 0.262). In addition, the proportion of taste cells predominantly sensitive to each of the four taste stimuli, and the grouping of taste cells based on hierarchical cluster analysis, were comparable with those of chorda tympani (CT) fibers. The occurrence of each class of taste cells with different taste responsiveness to the four taste stimuli was not significantly different from that of CT fibers except for classes with broad taste responsiveness. These results suggest that information derived from taste cells generating action potentials may provide the major component of taste information that is transmitted to gustatory nerve fibers. Copyright © 2006 The American Physiological Society.. |
| 64. | Tadahiro Ohkuri, Keiko Yasumatsu, Noriatsu Shigemura, Ryusuke Yoshida, Yuzo Ninomiya, Amiloride inhibition on NaCl responses of the chorda tympani nerve in two 129 substrains of mice, 129P3/J and 129X1/SvJ, Chemical Senses, 10.1093/chemse/bjj061, 31, 6, 565-572, 2006.07, Amiloride, a sodium channel blocker, is known to suppress NaCl responses of the chorda tympani (CT) nerve in various mammalian species. In mice, the NaCl suppressing effect of amiloride is reported to differ among strains. In C57BL mice, amiloride inhibits NaCl responses to about 50% of control, whereas no such clear suppression was evident in prior studies with 129 mice. However, evidence from behavioral studies is not entirely consistent with this. Recently, it has been found that genetic backgrounds of 129 mice differ within substrains. 129X1/SvJ (formerly 129/SvJ) mice differ from the 129P3/J (formerly 129/J) strain by 25% of sequence length polymorphisms. Therefore, we examined possible substrain difference between 129P3/J and 129X1/SvJ mice in the amiloride sensitivity of electrophysiologically recorded NaCl responses. Amiloride significantly suppressed CT responses to NaCl without affecting responses to KCl both in 129P3/J and 129X1/SvJ mice. However, the magnitude of the amiloride inhibition was significantly larger (∼50% of control in response to 0.01-1.0 M NaCl by 100 μM amiloride) in 129X1/SvJ than in 129P3/J mice (∼20% of control in response to 0.03-0.3 M NaCl by 100 μM amiloride). Threshold amiloride concentration for suppression of responses to 0.3 M NaCl was 30 μM in 129P3/J mice, which was higher than that in 129X1/SvJ mice (10 μM). In 129X1/SvJ mice, the threshold amiloride concentration eliciting inhibition of NaCl responses and the magnitude of the inhibition were comparable with those in C57BL/6 mice. These results suggest that amiloride sensitivity of NaCl responses differs even among the 129 substrains, 129P3/J and 129 X1/SvJ, and the substrain difference of 129 mice in amiloride sensitivity is as large as that between two inbred strains (129P3/J and C57BL/6). © 2006 Oxford University Press.. |
| 65. | Damak S, Rong M, Yasumatsu K, Kokrashvili Z, Perez CA, Shigemura N, Yoshida R, Mosinger B Jr, Glendinning JI, Ninomiya Y, Margolskee RF., Trpm5 null mice respond to bitter, sweet, and umami compounds. , Chem Senses, 31(3):253-64. , 2006.03. |
| 66. | Talavera K, Yasumatsu K, Voet T, Droogmans G, Shigemura N, Ninomiya Y, Margolskee RF, Nilius B., Heat-activation of the taste channel TRPM5 underlies thermal sensitivity to sweet., Nature, 438(7070):1022-5, 2005.12. |
| 67. | Shigemura N, Islam AA, Sadamitsu C, Yoshida R, Yasumatsu K, Ninomiya Y., Expression of amiloride-sensitive epithelial sodium channels in mouse taste cells after chorda tympani nerve crush., Chemical Senses, 10.1093/chemse/bji046, 30, 6, 531-538, 30(6):531-8, 2005.07. |
| 68. | Keisuke Sanematsu, Keiko Yasumatsu, Ryusuke Yoshida, Noriatsu Shigemura, Yuzo Ninomiya, Mouse strain differences in Gurmarin-sensitivity of sweet taste responses are not associated with polymorphisms of the sweet receptor gene, Tas1r3, Chemical Senses, 10.1093/chemse/bji041, 30, 6, 491-496, 2005.07, Gurmarin (Gur) is a peptide that selectively inhibits responses of the chorda tympani (CT) nerve to sweet compounds in rodents. In mice, the sweet-suppressing effect of Gur differs among strains. The inhibitory effect of Gur is clearly observed in C57BL/6 mice, but only slightly, if at all, in BALB/c mice. These two mouse strains possess different alleles of the sweet receptor gene, Sac(Tas1r3) (taster genotype for C57BL/6 and non-taster genotype for BALB/c mice), suggesting that polymorphisms in the gene may account for differential sensitivity to Gur. To investigate this possibility, we examined the effect of Gur in another Tas1r3 non-taster strain, 129X1/Sv mice. The results indicated that unlike non-taster BALB/c mice but similar to taster C57BL/6 mice, 129X1/Sv mice exhibited significant inhibition of CT responses to various sweet compounds by Gur. This suggests that the mouse strain difference in the Gur inhibition of sweet responses of the CT nerve may not be associated with polymorphisms of Tas1r3. © The Author 2005. Published by Oxford Universiry Press. All rights reserved.. |
| 69. | 城崎慎也、重村憲徳、吉田竜介、安松啓子、R.F.Margolskee、二ノ宮裕三, TRPM5-KOマウスのキニーネに対する行動応答の解析, 日本味と匂学会誌, 2005.01. |
| 70. | 安松啓子、斉藤幸子、MING DING、村田裕子、実松敬介、重村憲徳、R.F.Margolskee、二ノ宮裕三, 脂肪酸の苦味抑制効果：ヒト、マウス、ウシを用いた精神物理学的、分子生物学的、神経行動学的解析, 日本味と匂学会誌, 2005.01. |
| 71. | 吉田竜介、安松啓子、重村憲徳、二ノ宮裕三, 脳へ味を伝える：味のニューラルチャネルの形成, 日本味と匂学会誌, 2005.01. |
| 72. | 重村憲徳、小島博文、AA.シャヒドウル イスラム、中村由紀、城崎慎也、二ノ宮裕三, ヒト甘味感受性の多様性と遺伝子多型性についての解析, 日本味と匂学会誌, 2005.01. |
| 73. | Shigemura, N., Yasumatsu, K., Yoshida, R., Sako, N., Katsukawa, H., Nakashima K., Imoto, T., Ninomiya, Y., The role of the dpa locus in mice. Jan;30 (2005), Chemical Senses, 10.1093/chemse/bjh125, 30, I84-i85, Suppl 1:i84-i85, 2005.01. |
| 74. | Keiko Yasumatsu, Noriatsu Shigemura, Ryusuke Yoshida, Yuzo Ninomiya, Recovery of salt taste responses and PGP 9.5 immunoreactive taste bud cells during regeneration of the mouse chorda tympani nerve, Chemical Senses, 10.1093/chemse/bjh114, 30 SUPPL. 1, i62-3, 2005.01. |
| 75. | Ryusuke Yoshida, Keisuke Sanematsu, Noriatsu Shigemura, Keiko Yasumatsu, Yuzo Ninomiya, Taste receptor cells responding with action potentials to taste stimuli and their molecular expression of taste related genes, Chemical Senses, 10.1093/chemse/bjh092, 30 SUPPL. 1, i19-20, 2005.01. |
| 76. | 安松啓子、勝川英夫、重村憲徳、吉田竜介、二ノ宮裕三, 神経切断後の塩味情報システム再形成過程, 日本味と匂学会誌, 10(3): 389-392, 2003.12. |
| 77. | 吉田竜介、重村憲徳、安松啓子、二ノ宮裕三, 統計学的解析法による味刺激に対する味細胞の応答性の検討, 日本味と匂学会誌, 10(3): 659-662, 2003.12. |
| 78. | 重村憲徳、川東由利子、安松啓子、二ノ宮裕三, dpa（D-フェニルアラニン感受性）遺伝子セグメントの旨味感受性への関与, 日本味と匂学会誌, 10(3): 653-656, 2003.12. |
| 79. | Shigemura N, Ohta R, Kusakabe Y, Miura H, Hino A, Koyano K, Nakashima K, Ninomiya Y., Leptin modulates behavioral responses to sweet substances by influencing peripheral taste structures., Endocrinology, 10.1210/en.2003-0602, 145, 2, 839-847, 2003.10. |
| 80. | Rie Ohta, Noriatsu Shigemura, Kazushige Sasamoto, Kiyoshi Koyano, Yuzo Ninomiya, Conditioned taste aversion learning in leptin-receptor-deficient db/db mice, Neurobiology of Learning and Memory, 10.1016/S1074-7427(03)00046-7, 80, 2, 105-112, 2003.09, The db/db mouse has defective leptin receptors. The defects lead to impairments of leptin regulation of food intake and body weight, and result in the expression of diabetic symptoms such as hyperinsulinemia, hyperglicemia, and extreme obesity. Recent studies have proposed that leptin may also affect memory and learning processes. To examine this possibility, we compared the ability of leptin-receptor-deficient db/db mice and their normal lean litter mates to form and extinguish a conditioned taste aversion (CTA) for saccharin. We used a short-term (10s) lick test and a long-term (48h) two bottle preference test for measurement of consumption of test solutions. On the first day after conditioning to avoid saccharin, the db/db mice showed preference scores for saccharin as low, and aversion thresholds for sucrose lower than that of the lean mice. During the extinction test trials beginning from the second up to the 30th day after conditioning, numbers of licks and preference scores for aversive saccharin and sucrose appeared to be larger, and recovered faster to the control levels in db/db mice. These results indicate that db/db mice with leptin-receptor-deficiency may show equal capacity to form CTAs for saccharin, greater generalization from saccharin to sucrose, and a faster rate of extinction. This suggests that disruption of leptin signalling does not inhibit acquisition of CTA learning, but impairs its extinction. This differential contribution of the leptin system on CTA processes may be due to differential distribution of leptin receptors in the CTA-related brain areas. © 2003 Elsevier Science (USA). All rights reserved.. |
| 81. | Shigemura N, Miura H, Kusakabe Y, Hino A, Ninomiya Y., Expression of leptin receptor (Ob-R) isoforms and signal transducers and activators of transcription (STATs) mRNAs in the mouse taste buds., Arch Histol Cytol., 10.1679/aohc.66.253, 66, 3, 253-260, 66(3):253-60., 2003.08. |
| 82. | Yuko Murata, Kiyohito Nakashima, Ayako Yamada, Noriatsu Shigemura, Kazushige Sasamoto, Yuzo Ninomiya, Gurmarin suppression of licking responses to sweetener-quinine mixtures in C57BL mice, Chemical Senses, 10.1093/chemse/28.3.237, 28, 3, 237-243, 2003.03, Gurmarin (Gur) is a peptide that selectively suppresses responses of the chorda tympani nerve to sweet substances in rats and mice. In the present study, we examined the effect of Gur on behavioral responses to sweet substances in C57BL mice. To accomplish this, we developed a new short-term lick test and measured numbers of licks for 10 s for sweet substances mixed with quinine hydrochloride (QHCI) in water-deprived mice. Numbers of licks for sucrose mixed with 1 or 3 mM QHCI increased with increasing concentration of sucrose from 0.01 to 1.0 M. Oral infusion with 30 μg/ml Gur produced significant decreases in responses to concentration series for sucrose mixed with 3 mM QHCI, whereas no such effect by Gur was observed in responses to QHCI alone or QHCI-mixed HCI, NaCI or monosodium glutamate. The Gur suppression of QHCI-mixed sucrose responses, which otherwise lasted for 2-3 h, rapidly returned to ∼80% of control levels after oral infusion with β-cyclodextrin. These results are comparable to neural data previously found in chorda tympani responses, and thereby provide further evidence for Gur as a sweet response inhibitor in C57BL mice. In the other aspect, our newly developed short-term test can also provide a tool for measurements of taste-guided behavioral responses to sweeteners. © Oxford University Press 2003. All rights reserved.. |
| 83. | 古田洋樹、鈴木亨、川東由利子、重村憲徳、笹本一茂、二ノ宮裕三, 近交系マウスを用いたうま味物質MSGに対する行動応答解析, 日本味と匂学会誌, 9(3) 721-724, 2002.12. |
| 84. | 太田理絵、重村憲徳、古谷野潔、二ノ宮裕三, ヒト味覚閾値、血清レプチン、血糖値の概日リズムとそれらの相関性について, 日本味と匂学会誌, 9(3) 573-576, 2002.12. |
| 85. | 重村憲徳、川東由利子、笹本一茂、二ノ宮裕三, dpa（D-フェニルアラニン感受性）コンジェニックマウスにおけるdpa遺伝子セグメントの特性, 日本味と匂学会誌, 9 (3): 465-468, 2002.12. |
| 86. | Kumiko Sugimoto, Noriatsu Shigemura, Keiko Yasumatsu, Rie Ohta, Kiyohito Nakashima, Kirio Kawai, Yuzo Ninomiya, Ion channels and second messengers involved in transduction and modulation of sweet taste in mouse taste cells, Pure and Applied Chemistry, 10.1351/pac200274071141, 74, 7, 1141-1151, 2002.07, Leptin, a hormone released from the adipose tissue, inhibits food intake and increases energy expenditure. We have found a novel function of leptin as a modulator of sweet taste sensitivity in mice. In lean normal mice, the gustatory nerve responses to sweet stimuli were selectively suppressed depending on plasma leptin level after an intraperitoneal injection of recombinant leptin. Patch-clamp studies using isolated taste cells of lean mice showed that extracellular leptin enhanced K+ currents of sweet-responsive taste cells, which led to membrane hyperpolarization and a reduction of sweetener-induced depolarization. Reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization analyses demonstrated specific expression of mRNA of the long-form functional leptin receptor (Ob-Rb) in taste tissue and cells of lean mice. The genetically diabetic db/db mice, which have defects in Ob-Rb, demonstrated neither a suppression of gustatory neural responses to sweeteners nor an increment of whole-cell K+ conductance of taste cells even with high doses of leptin. These results suggest that Ob-Rb is specifically expressed in sweet-responsive taste cells of lean mice and that leptin suppresses sweetener-induced depolarization via activation of K+ channels, leading to a decrease in impulses of sweet-best fibers. The enhanced sweet responses of db/db mice may result from the lack of inhibitory modulation by leptin.. |
| 87. | Ninomiya, Y., Shigemura, N., Yasumatsu, K., Ohta, R., Sugimoto, K., Nakashima, K. and Lindemann, B., Leptin and sweet taste., Vitam. Horm., 10.1016/S0083-6729(02)64007-5, 64, 221-248, 64: 221-247, 2002.05. |
| 88. | 貞光千春、安松啓子、重村憲徳、二ノ宮裕三, マウス有郭及び茸状乳頭におけるアミロライド感受性Na+チャネルの発現, 日本味と匂学会誌, 8 (3): 605-608, 2001.12. |
| 89. | 鈴木亨、重村憲徳、日下部裕子、日野明寛、二ノ宮裕三, 近交系及びそれらの交雑群を用いたマウス甘味応答の行動遺伝学的解析, 日本味と匂学会誌, 8 (3): 635-638, 2001.12. |
| 90. | 重村憲徳、三浦裕仁、日野明寛、二ノ宮裕三, マウス舌味蕾におけるレプチン受容体とSTAT3の発現, 日本味と匂学会誌, 8 (3): 627-630, 2001.12. |
| 91. | Shigemura N, Kiyoshima T, Sakai T, Matsuo K, Momoi T, Yamaza H, Kobayashi I, Wada H, Akamine A, Sakai H., Localization of activated caspase-3-positive and apoptotic cells in the developing tooth germ of the mouse lower first molar., Histochem J., 10.1023/A:1017900305661, 33, 5, 253-258, 33(5):253-8., 2001.05. |
| 92. | 太田理絵、中島清人、重村憲徳、古谷野潔、二ノ宮裕三, レプチンの甘味抑制効果遺伝的肥満糖尿病db/db及びob/obマウスの行動応答解析, 日本味と匂学会誌, 8 (3): 631-634, 2001.01. |
| 93. | 重村憲徳、二ノ宮裕三, 甘味感受性と肥満, Techno Innovation, 11 (4): 25-31, 2001.01. |
| 94. | Yamaza H, Matsuo K, Kiyoshima T, Shigemura N, Kobayashi I, Wada H, Akamime A, Sakai H., Detection of differentially expressed genes in the early developmental stage of the mouse mandible., Int J Dev Biol., 45, 4, 675-680, 45(4):675-80, 2001.01. |
| 95. | 重村憲徳,三浦裕仁,日下部裕子,日野明寛,中島清人,杉本久美子,二ノ宮裕三, マウス舌味蕾におけるレプチン受容体の発現と味神経甘味応答の抑制, 日本味と匂学会誌, Vol.7,No.3,pp.559-562, 2000.01. |
| 96. | Ieyoshi Kobayashi, Tamotsu Kiyoshima, Satoru Ozeki, Kaori Shima, Noriatsu Shigemura, Kou Matsuo, Hidetaka Sakai, Immunohistochemical and ultrastructural study of a papillary cystadenocarcinoma arising from the sublingual gland, Journal of Oral Pathology and Medicine, 10.1111/j.1600-0714.1999.tb02040.x, 28, 6, 282-286, 1999.07, Immunohistochemical and ultrastructural findings in a rare case of papillary cyst-adenocarcinoma arising from the left sublingual gland of a 55-year-old Japanese man are reported. Histologically, the tumor tissue was found to be composed of various-sized cystic cavities in which papillary epithelial projections with thin fibrovascular cores were observed. The papillary projections consisted of a single layer to several layers of high columnar epithelial cells. Invasion to the surrounding fibrous tissue and into the lymphatics was observed, thus suggesting an aggressive potential in the present case. The possibility of the involvement of myoepithelial cells could be excluded based on the immunohistochemical and ultrastructural findings. The immunohistochemical and ultrastructural findings also suggested that this type of salivary gland tumor, at least the present case, may arise from striated or excretory ducts. There was positive immunostaining for tumor markers CA19-9 and CA125. However, the biological role of these carbohydrate antigens in salivary gland tumors is unclear at present. Further investigations are, therefore, called for to solve this issue.. |
| 97. | Shigemura N, Kiyoshima T, Kobayashi I, Matsuo K, Yamaza H, Akamine A, Sakai H., The distribution of BrdU- and TUNEL-positive cells during odontogenesis in mouse lower first molars., Histochem. J., 10.1023/A:1003796023992, 31, 6, 367-377, 31 (6): 367-377, 1999.01. |
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