Kyushu University [Noriatsu Shigemura (Professor) Faculty of Dental Science, Department of Dental Science]

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Noriatsu Shigemura
Professor
Oral Biological Sciences
Department of Dental Science
Faculty of Dental Science
Last modified date：2024.04.26

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Department of Dental Science
Graduate School of Dental Science

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Department of Dentistry
School of Dentistry

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Research and Development Center for Five-Sense Devices

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Total Priod of education and research career in the foreign country

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1.	Hirayama A, Iwata S, Oike A, Kawabata Y, Nagasato Y, Takai S, Sanematsu K, Takahashi I, Shigemura N., Cellular mechanisms of taste disturbance induced by the non-steroidal anti-inflammatory drug, diclofenac, in mice., Front Cell Neurosci., 10.3389/fncel.2023.1279059, 17, 1279059, 2023.12, Drug-induced taste disorders are a serious problem in an aging society. This study investigated the mechanisms underlying taste disturbances induced by diclofenac, a non-steroidal anti-inflammatory drug that reduces pain and inflammation by inhibiting the synthesis of prostaglandins by cyclooxygenase enzymes (COX-1 and COX-2). RT-PCR analyses demonstrated the expression of genes encoding arachidonic acid pathway components such as COX-1, COX-2 and prostaglandin synthases in a subset of mouse taste bud cells. Double-staining immunohistochemistry revealed that COX-1 and cytosolic prostaglandin E synthase (cPGES) were co-expressed with taste receptor type-1 member-3 (T1R3), a sweet/umami receptor component, or gustducin, a bitter/sweet/umami-related G protein, in a subset of taste bud cells. Long-term administration of diclofenac reduced the expression of genes encoding COX-1, gustducin and cPGES in mouse taste buds and suppressed both the behavioral and taste nerve responses to sweet and umami taste stimuli but not to other tastants. Furthermore, diclofenac also suppressed the responses of both mouse and human sweet taste receptors (T1R2/T1R3, expressed in HEK293 cells) to sweet taste stimuli. These results suggest that diclofenac may suppress the activation of sweet and umami taste cells acutely via a direct action on T1R2/T1R3 and chronically via inhibition of the COX/prostaglandin synthase pathway inducing down-regulated expression of sweet/umami responsive components. This dual inhibition mechanism may underlie diclofenac-induced taste alterations in humans. .
2.	Kawabata Y, Takai S, Sanematsu K, Yoshida R, Kawabata F, Shigemura N., The Antiarrhythmic Drug Flecainide Enhances Aversion to HCl in Mice. , eNeuro. , 10.1523/ENEURO.0048.2023, 10, (9), ENEURO.0048--23, 2023.09, Drug-induced taste disorders reduce quality of life, but little is known about the molecular mechanisms by which drugs induce taste disturbances. In this study, we investigated the short-term and long-term effects of the antiarrhythmic drug flecainide, which is known to cause taste dysfunction. Analyses of behavioral responses (licking tests) revealed that mice given a single intraperitoneal injection of flecainide exhibited a significant reduction in preference for a sour tastant (HCl) but not for other taste solutions (NaCl, quinine, sucrose, KCl and monopotassium glutamate) when compared with controls. Mice administered a single dose of flecainide also had significantly higher taste nerve responses to HCl but not to other taste solutions. Compared with controls, mice administered flecainide once-daily for 30 d showed a reduced preference for HCl without any changes in the behavioral responses to other taste solutions. The electrophysiological experiments using HEK293T cells transiently expressing otopetrin-1 (Otop1; the mouse sour taste receptor) showed that flecainide did not alter the responses to HCl. Taken together, our results suggest that flecainide specifically enhances the response to HCl in mice during short-term and long-term administration. Although further studies will be needed to elucidate the molecular mechanisms, these findings provide new insights into the pathophysiology of drug-induced taste disorders. .
3.	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.
4.	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.
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.
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.
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, 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, 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.	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.
10.	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, 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..
11.	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, 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..
12.	Noriatsu Shigemura, Yuzo Ninomiya, Recent Advances in Molecular Mechanisms of Taste Signaling and Modifying., Int Rev Cell Mol Biol., 323, 71-106, 2016.02.
13.	Noriatsu Shigemura, Modulation of Taste Responsiveness by Angiotensin II., Food Science and Technology Research, 21 , 6, 757-764, 2015.06.
14.	Noriatsu Shigemura, Angiotensin II and taste sensitivity., Japanese Dental Science Review, 51, 2, 51-8, 2015.05.
15.	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。.
16.	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.
17.	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.
18.	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.
19.	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.
20.	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.
21.	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.
22.	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.
23.	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.
24.	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.
25.	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.
26.	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.
27.	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.

1.	Shigemura N, Taste renin-angiotensin system may contribute to the maintenance of sodium homeostasis, 第68回JADR総会・学術大会, 2020.11, 本学会は、国際歯科研究学会（International Association for Dental Research：IADR）のSectionとして1954年11月6日に発足し、その後、会員の増加と活発な学会活動が認められIADRのDivisionに昇格し、Japanese Association for Dental Research（JADR）と称して今日に至っています。そして現在では、IADRのDivision/Sectionの中で世界第2位の規模を誇り、世界をリードする学術活動を展開しています。JADRは、その設立以来、歯科医学および関連分野の研究の促進を図り、口腔保健の向上に寄与するとともに、国際的視野にたってIADR の発展に貢献し、社会の公益に寄与することを目的としてきました。.
2.	Noriatsu Shigemura, Ryusuke Yoshida, Keiko Yasumatsu, Tadahiro Ohkuri, Shusuke Iwata, Shingo Takai, Masafumi Jyotaki, Mayu Niki, Keisuke Sanematsu, Yuzo Ninomiya, Hormonal modulation of salty and sweet taste sensitivities., The 91st Annual Meeting of the Physiology Society of Japan, 2014.03, 血圧を調節する鍵ホルモンであるアンジオテンシンIIは、中枢性に作用して塩分嗜好性を増強するのみならず、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増加させることを明らかにした。また摂食調節因子であるレプチンと内因性カンナビノイドは中枢性に拮抗的に働くだけでなく、味覚器にも作用し、甘味感受性を拮抗的に調節することで、エネルギー摂取量を制御していることを明らかにした。以上のことから、新たなホルモンを介した脳-味覚連関による合目的な体内栄養維持機構が存在する可能性が示唆された。.
3.	Noriatsu Shigemura, Taste perception and food intake, 86th Annual meeting of the Japanese Pharmalogical Society, 2013.03, Information derived from taste receptor cells, such as sweet, bitter, salty, sour and umami is important for evaluating the quality of food components. Modulation of the gustatory information influences food preference and intake. Even so, the molecular mechanisms for modulating taste sensitivity are poorly understood. Our recent studies have demonstrated that sweet and salty taste sensitivities are affected by hormones. Angiotensin II (AngII), which plays important roles in the maintenance of sodium homeostasis by acting on AngII type 1 receptor in various organs including brain and kidney, modulates peripheral salt and sweet taste sensitivities, and this modulation influences ingestive behavior in mice. Leptin (an anorexigenic mediator) and endocannabinoids (orexigenic mediators), which reciprocally regulate food intake via central nervous systems, modulate palatability of foods by altering sweet taste responses. Thus peripheral modulations of taste information by these hormones critically influence food intake, and may play important roles in regulating sodium and energy homeostasis. Understanding basic principles about these taste modulations may lead us to design novel strategies to maintain and improve the quality of life in patients with medical treatment..
4.	The dpa locus may influence behavioral and neural responses to umami Noriatsu Shigemura1, Keiko Yasumatsu1,2 , Yuriko Kawato1,2 , and Yuzo Ninomiya 1,2 (1 Sect. of Oral Neurosci., Grad. Sch. of Dent. Sci., Kyushu Univ., 2 BRAIN).
5.	Behavioral and molecular analyses in the dpa (D-phenylalanine sensitivity) congenic strain Shigemura Noriatsu1, Kawato Yuriko1, Furuta Hiroki2, Yoshida Ryusuke2, and Ninomiya Yuzo2 1Sect. Oral Neurosci., Grad. Sch. Dental Sci., Kyushu Univ., Fukuoka, Japan, 2Bio-oriented Tech. Res. Adv. Ins. (BRAIN), Saitama, Japan; shigemura@dent.kyushu-u.ac.jp.