Misawa, Hidemi



Faculty of Pharmacy, Department of Pharmaceutical Sciences 薬理学講座 (Shiba-Kyoritsu)



E-mail Address

E-mail address

External Links

Other Affiliation 【 Display / hide

  • Dean, Faculty of Pharmacy

  • Dean, Graduate School of Pharmaceutical Sciences

Career 【 Display / hide

  • 1989.04

    Research Scientist, Tokyo Metropolitan Institute for Neuroscience

  • 1998.04

    University of California at San Francisco, Visiting Scientist

  • 2001.04

    Senior Research Scientist, Tokyo Metropolitan Institute for Neuroscience

  • 2005.04

    Kyoritsu University of Pharmacy, Associate Professor

  • 2007.04

    Kyoritsu University of Pharmacy, Professor

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Academic Background 【 Display / hide

  • 1987.03

    Kyoto University, Faculty of Pharmaceutical Science

    University, Graduated

  • 1989.03

    Kyoto University, Graduate School, Division of Pharmaceutical Sciences

    Graduate School, Completed, Master's course

Academic Degrees 【 Display / hide

  • 博士(薬学), Kyoto University, Dissertation, 1993.07


Research Areas 【 Display / hide

  • Neurochemistry/Neuropharmacology (Nerve Chemistry/Nerve Pharmacology)


Books 【 Display / hide

  • スタンダード薬学シリーズ Ⅱ-9 薬学演習 Ⅰ. 医療薬学・臨床薬学

    日本薬学会編 三澤日出巳 他, 東京化学同人, 2020.10

  • 臨床薬学テキストシリーズ「神経・筋・精神 / 麻酔・鎮痛」

    三澤日出巳、山下博史, 中山書店, 2019.08

    Scope: 筋萎縮性側索硬化症,  Contact page: 151-156

  • 脳内環境辞典

    三澤 日出巳, メディカルドゥ, 2017.03

    Scope: オステオポンチン

  • グッドマン・ギルマン薬理書:薬物治療の基礎と臨床 12版

    三澤 日出巳, 廣川書店, 2013.04

    Scope: 314-339

  • ブレインサイエンス・レビュー2010

    三澤日出巳, 東京/クバプロ, 2010.03

    Scope: 237-258

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Papers 【 Display / hide

  • Regulation of immune functions by non-neuronal acetylcholine (Ach) via muscarinic and nicotinic ach receptors

    Mashimo M., Moriwaki Y., Misawa H., Kawashima K., Fujii T.

    International Journal of Molecular Sciences (International Journal of Molecular Sciences)  22 ( 13 )  2021.07

    ISSN  16616596

     View Summary

    Acetylcholine (ACh) is the classical neurotransmitter in the cholinergic nervous system. However, ACh is now known to regulate various immune cell functions. In fact, T cells, B cells, and macrophages all express components of the cholinergic system, including ACh, muscarinic, and nicotinic ACh receptors (mAChRs and nAChRs), choline acetyltransferase, acetylcholinesterase, and choline transporters. In this review, we will discuss the actions of ACh in the immune system. We will first briefly describe the mechanisms by which ACh is stored in and released from immune cells. We will then address Ca2+ signaling pathways activated via mAChRs and nAChRs on T cells and B cells, highlighting the importance of ACh for the function of T cells, B cells, and macrophages, as well as its impact on innate and acquired (cellular and humoral) immunity. Lastly, we will discuss the effects of two peptide ligands, secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1) and hippocampal cholinergic neurostimulating peptide (HCNP), on cholinergic activity in T cells. Overall, we stress the fact that ACh does not function only as a neurotransmitter; it impacts immunity by exerting diverse effects on immune cells via mAChRs and nAChRs.

  • Competitive inhibition of the high-affinity choline transporter by tetrahydropyrimidine anthelmintics

    Okuda T., Nomura Y., Konishi A., Misawa H.

    European Journal of Pharmacology (European Journal of Pharmacology)  898   173986 2021.05

    ISSN  00142999

     View Summary

    The high-affinity choline transporter CHT1 mediates choline uptake, the rate-limiting and regulatory step in acetylcholine synthesis at cholinergic presynaptic terminals. CHT1-medated choline uptake is specifically inhibited by hemicholinium-3, which is a type of choline analog that acts as a competitive inhibitor. Although the substrate choline and the inhibitor hemicholinium-3 are well-established ligands of CHT1, few potent ligands other than choline analogs have been reported. Here we show that tetrahydropyrimidine anthelmintics, known as nicotinic acetylcholine receptor agonists, act as competitive inhibitors of CHT1. A ligand-dependent trafficking assay in cell lines expressing human CHT1 was designed to search for CHT1 ligands from a collection of biologically active compounds. We found that morantel as well as other tetrahydropyrimidines, pyrantel and oxantel, potently inhibits the high-affinity choline uptake activity of CHT1 in a competitive manner similar to the inhibitor hemicholinium-3. They also inhibit the high-affinity choline transporter from the nematode Caenorhabditis elegans. Finally, tetrahydropyrimidines potently inhibit the high-affinity choline uptake in rat brain synaptosomes at a low micromolar level, resulting in the inhibition of acetylcholine synthesis. The rank order of potency in synaptosomes is as follows: morantel > pyarantel > oxantel (Ki = 1.3, 5.7, and 8.3 μM, respectively). Our results reveal that tetrahydropyrimidine anthelmintics are novel CHT1 ligands that inhibit the high-affinity choline uptake for acetylcholine synthesis in cholinergic neurons.

  • Endogenous neurotoxin-like protein Ly6H inhibits alpha7 nicotinic acetylcholine receptor currents at the plasma membrane

    Moriwaki Y., Kubo N., Watanabe M., Asano S., Shinoda T., Sugino T., Ichikawa D., Tsuji S., Kato F., Misawa H.

    Scientific Reports (Scientific Reports)  10 ( 1 ) 11996 2020.12

     View Summary

    © 2020, The Author(s). α7 nicotinic acetylcholine receptors (nAChRs) are widely expressed in the central nervous system and regarded as potential therapeutic targets for neurodegenerative conditions, such as Alzheimer’s disease and schizophrenia. Yet, despite the assumed pathophysiological importance of the α7 nAChR, molecular physiological characterization remains poorly advanced because α7 nAChR cannot be properly folded and sorted to the plasma membranes in most mammalian cell lines, thus preventing the analyses in heterologous expression system. Recently, ER-resident membrane protein NACHO was discovered as a strong chaperone for the functional expression of α7 nAChR in non-permissive cells. Ly6H, a brain-enriched GPI-anchored neurotoxin-like protein, was reported as a novel modulator regulating intracellular trafficking of α7 nAChR. In this study, we established cell lines that stably and robustly express surface α7 nAChR by introducing α7 nAChR, Ric-3, and NACHO cDNA into HEK293 cells (Triple α7 nAChR/RIC-3/NACHO cells; TARO cells), and re-evaluated the function of Ly6H. We report here that Ly6H binds with α7 nAChRs on the cell membrane and modulates the channel activity without affecting intracellular trafficking of α7 nAChR.

  • Behavioral and electrophysiological evidence for a neuroprotective role of aquaporin-4 in the 5xFAD transgenic mice model

    Abe Y., Ikegawa N., Yoshida K., Muramatsu K., Hattori S., Kawai K., Murakami M., Tanaka T., Goda W., Goto M., Yamamoto T., Hashimoto T., Yamada K., Shibata T., Misawa H., Mimura M., Tanaka K.F., Miyakawa T., Iwatsubo T., Hata J.I., Niikura T., Yasui M.

    Acta Neuropathologica Communications (Acta Neuropathologica Communications)  8 ( 1 ) 67 2020.05

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    © 2020 The Author(s). Aquaporin-4 (AQP4) has been suggested to be involved in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), which may be due to the modulation of neuroinflammation or the impairment of interstitial fluid bulk flow system in the central nervous system. Here, we show an age-dependent impairment of several behavioral outcomes in 5xFAD AQP4 null mice. Twenty-four-hour video recordings and computational analyses of their movement revealed that the nighttime motion of AQP4-deficient 5xFAD mice was progressively reduced between 20 and 36 weeks of age, with a sharp deterioration occurring between 30 and 32 weeks. This reduction in nighttime motion was accompanied by motor dysfunction and epileptiform neuronal activities, demonstrated by increased abnormal spikes by electroencephalography. In addition, all AQP4-deficient 5xFAD mice exhibited convulsions at least once during the period of the analysis. Interestingly, despite such obvious phenotypes, parenchymal amyloid β (Aβ) deposition, reactive astrocytosis, and activated microgliosis surrounding amyloid plaques were unchanged in the AQP4-deficient 5xFAD mice relative to 5xFAD mice. Taken together, our data indicate that AQP4 deficiency greatly accelerates an age-dependent deterioration of neuronal function in 5xFAD mice associated with epileptiform neuronal activity without significantly altering Aβ deposition or neuroinflammation in this mouse model. We therefore propose that there exists another pathophysiological phase in AD which follows amyloid plaque deposition and neuroinflammation and is sensitive to AQP4 deficiency.

  • Minireview: Divergent roles of α7 nicotinic acetylcholine receptors expressed on antigen-presenting cells and CD4<sup>+</sup> T cells in the regulation of T cell differentiation

    Mashimo M., Fujii T., Ono S., Moriwaki Y., Misawa H., Kawashima K.

    International Immunopharmacology (International Immunopharmacology)  82   106306 2020.05

    ISSN  15675769

     View Summary

    © 2020 Elsevier B.V. α7 nAChRs expressed on immune cells regulate antigen-specific antibody and proinflammatory cytokine production. Using spleen cells from ovalbumin (OVA)-specific T cell receptor transgenic DO11.10 mice and the α7 nAChR agonist GTS-21, investigation of (1) antigen processing-dependent and (2) -independent, antigen presenting cell (APC)-dependent, naïve CD4+ T cell differentiation, as well as (3) non-specific APC-independent, anti-CD3/CD28 mAbs-induced CD4+ T cell differentiation, revealed the differential roles of α7 nAChRs expressed on T cells and APCs in the regulation of CD4+ T cell differentiation. GTS-21 suppressed OVA-induced antigen processing- and APC-dependent differentiation into regulatory T cells (Tregs) and effector T cells (Th1, Th2 and Th17) without affecting OVA uptake or cell viability. By contrast, GTS-21 upregulated OVA peptide-induced antigen processing-independent T cell differentiation into all lineages. During anti-CD3/CD28 mAbs-induced T cell differentiation in the presence of polarizing cytokines, GTS-21 promoted wild-type T cell differentiation into all lineages, but did not affect α7 nAChR-deficient T cell differentiation. These results demonstrate (1) that α7 nAChRs on APCs downregulate T cell differentiation by inhibiting antigen processing and thereby interfering with antigen presentation; and (2) that α7 nAChRs on T cells upregulate differentiation into Tregs and effector T cells. Thus, the divergent roles of α7 nAChRs on APCs and T cells likely regulate the intensity of immune responses. These findings suggest the possibility of using α7 nAChR agonists to harvest greater numbers of Tregs and Th1 and Th2 cells for adoptive immune therapies for treatment of autoimmune diseases and cancers.

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Papers, etc., Registered in KOARA 【 Display / hide

Reviews, Commentaries, etc. 【 Display / hide

  • 脂質代謝調節による神経再生への寄与

    米津好乃, 三澤日出巳, 村松里衣子

    日薬理誌 (日本薬理学会)  155   354 - 354 2020.09

    Introduction and explanation (scientific journal), Joint Work

  • 運動ニューロンサブタイプとALSにおける選択的脆弱性の解析


    日薬理誌 (日本薬理学会)  152   64 - 69 2018.08

    Introduction and explanation (scientific journal), Joint Work

  • コリン:ニューロンにおける機能


    CLINICAL NEUROSCIENCE (中外医学社)  36 ( 6 ) 656 - 659 2018.06

    Introduction and explanation (scientific journal), Joint Work

  • 疾患モデル動物を用いた精神医学研究の展望


    精神科 (科学評論社)  30 ( 3 ) 221 - 266 2017.03

    Introduction and explanation (scientific journal), Joint Work

  • 筋萎縮性側索硬化症 (ALS) の原因究明と治療に向けた基礎研究

    三澤 日出巳、新倉麻己子

    基礎老化研究 38 ( 1 ) 19 - 25 2014.02

    Introduction and explanation (scientific journal), Joint Work

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Presentations 【 Display / hide

  • 運動ニューロンのサブタイプと生理・病態


    基盤医学特論 (名古屋市) , 2019.10, Public discourse, seminar, tutorial, course, lecture and others, 名古屋大学環境医学研究所

  • Postnatal selective elimination of slow-type motor neurons induces late-onset neuromuscular deficits in mice: Red muscle atrophy, posture abnormality and kinetic tremor.

    Kamishima K, Koyama T, Ohgaki L, Yamanaka T, Itohara S, Ogihara N, Sawano S, Mizunoya W, Misawa H.

    Neuroscience 2019 (Chicago) , 2019.10, Poster (general)

  • アルファー7型ニコチン受容体に対する新たな内在性修飾因子Ly6Hの作用機構: GPIアンカーの必要性

    浅野慎介, 森脇康博, 渡邊みずほ, 久保那月, 加藤総夫, 三澤日出巳.

    第140回日本薬理学会関東部会 (東京都) , 2019.07, Oral Presentation(general)

  • 抗原提示細胞上に発現するアルファー7ニコチン性アセチルコリン受容体 (alpha7 nAChR)は, CD4+ T細胞の分化を抑制する

    村瀬真美, 間下雅士, 小森眞紗代, 藤井健志, 小野史郎, 森脇康博, 三澤日出巳, 川島紘一郎.

    第92回日本薬理学会年会 (大阪市) , 2019.03, Poster (general)

  • 悪性中皮腫の新規マーカーHEG1に対するモノクローナル抗体の作製

    加藤嵩大, 森脇康博, 三澤日出巳, 辻祥太郎.

    第92回日本薬理学会年会, 2019.03, Poster (general)

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Research Projects of Competitive Funds, etc. 【 Display / hide

  • 神経変性疾患における毒性タンパク質の細胞間伝播とグリアリンパ系の関与


    MEXT,JSPS, Grant-in-Aid for Scientific Research, 三澤 日出巳, Grant-in-Aid for Scientific Research (C), Principal Investigator

  • Crisis management systems by neurons to defend against systemic immune storms


    MEXT,JSPS, Grant-in-Aid for Scientific Research, 三澤 日出巳, Grant-in-Aid for Challenging Exploratory Research, Principal Investigator


Courses Taught 【 Display / hide











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