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TRPM7 is mechanosensitive volume-regulatory cation channel in human epithelial cells
Tomohiro Numata
2006年03月 [査読有り]
単著
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Tagashira H.
Journal of Pharmacological Sciences ( Journal of Pharmacological Sciences ) 151 ( 2 ) 128 - 133 2023年02月
研究論文（学術雑誌）
The Sigma-1 receptor (Sigmar1) is downregulated in heart failure model mice with mitochondrial dysfunction. However, the mechanism in detail has not been investigated. In this study, we investigated the role of Sigmar1 in ER-mitochondria proximity using Sigmar1-knockdown or -overexpressed neonatal rat ventricular myocytes (NRVMs). The endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy was aggravated with the dysregulation of mitochondrial function and ER-mitochondrial junctional formation in Sigmar1-knockdown NRVMs, whereas improved in Sigmar1 overexpressed NRVMs. Our data suggests that the reduction of the cardiac Sigmar1 results in decrease mitochondrial Ca2+ influx and promotes mitochondrial fission, followed by reduced ER-mitochondria proximity, exacerbating ET-1-induced cardiomyocyte injury.
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Intermediate conductance Ca2+-activated potassium channels are activated by functional coupling with stretch-activated nonselective cation channels in cricket myocytes
Tomohiro Numata, Kaori Sato-Numata, Masami Yoshino
Frontiers in Insect Science ( Frontiers Media {SA} ) 2 2023年01月
研究論文（学術雑誌）
<jats:p>Cooperative gating of localized ion channels ranges from fine-tuning excitation–contraction coupling in muscle cells to controlling pace-making activity in the heart. Membrane deformation resulting from muscle contraction activates stretch-activated (SA) cation channels. The subsequent Ca<jats:sup>2+</jats:sup> influx activates spatially localized Ca<jats:sup>2+</jats:sup>-sensitive K<jats:sup>+</jats:sup> channels to fine-tune spontaneous muscle contraction. To characterize endogenously expressed intermediate conductance Ca<jats:sup>2+</jats:sup>-activated potassium (IK) channels and assess the functional relevance of the extracellular Ca<jats:sup>2+</jats:sup> source leading to IK channel activity, we performed patch-clamp techniques on cricket oviduct myocytes and recorded single-channel data. In this study, we first investigated the identification of IK channels that could be distinguished from endogenously expressed large-conductance Ca<jats:sup>2+</jats:sup>-activated potassium (BK) channels by adding extracellular Ba<jats:sup>2+</jats:sup>. The single-channel conductance of the IK channel was 62 pS, and its activity increased with increasing intracellular Ca<jats:sup>2+</jats:sup> concentration but was not voltage-dependent. These results indicated that IK channels are endogenously expressed in cricket oviduct myocytes. Second, the Ca<jats:sup>2+</jats:sup> influx pathway that activates the IK channel was investigated. The absence of extracellular Ca<jats:sup>2+</jats:sup> or the presence of Gd<jats:sup>3+</jats:sup> abolished the activity of IK channels. Finally, we investigated the proximity between SA and IK channels. The removal of extracellular Ca<jats:sup>2+</jats:sup>, administration of Ca<jats:sup>2+</jats:sup> to the microscopic region in a pipette, and application of membrane stretching stimulation increased SA channel activity, followed by IK channel activity. Membrane stretch-induced SA and IK channel activity were positively correlated. However, the emergence of IK channel activity and its increase in response to membrane mechanical stretch was not observed without Ca<jats:sup>2+</jats:sup> in the pipette. These results strongly suggest that IK channels are endogenously expressed in cricket oviduct myocytes and that IK channel activity is regulated by neighboring SA channel activity. In conclusion, functional coupling between SA and IK channels may underlie the molecular basis of spontaneous rhythmic contractions.</jats:p>
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Cardioprotective effects of Moku-boi-to and its impact on AngII-induced cardiomyocyte hypertrophy
Tagashira H.
Frontiers in Cell and Developmental Biology ( Frontiers in Cell and Developmental Biology ) 11 1264076 - 1264076 2023年
研究論文（学術雑誌）
Cardiomyocyte hypertrophy, induced by elevated levels of angiotensin II (AngII), plays a crucial role in cardiovascular diseases. Current therapeutic approaches aim to regress cardiac hypertrophy but have limited efficacy. Widely used Japanese Kampo medicines are highly safe and potential therapeutic agents. This study aims to explore the impact and mechanisms by which Moku-boi-to (MBT), a Japanese Kampo medicine, exerts its potential cardioprotective benefits against AngII-induced cardiomyocyte hypertrophy, bridging the knowledge gap and contributing to the development of novel therapeutic strategies. By evaluating the effects of six Japanese Kampo medicines with known cardiovascular efficiency on AngII-induced cardiomyocyte hypertrophy and cell death, we identified MBT as a promising candidate. MBT exhibited preventive effects against AngII-induced cardiomyocyte hypertrophy, cell death and demonstrated improvements in intracellular Ca2+ signaling regulation, ROS production, and mitochondrial function. Unexpectedly, experiments combining MBT with the AT1 receptor antagonist losartan suggested that MBT may target the AT1 receptor. In an isoproterenol-induced heart failure mouse model, MBT treatment demonstrated significant effects on cardiac function and hypertrophy. These findings highlight the cardioprotective potential of MBT through AT1 receptor-mediated mechanisms, offering valuable insights into its efficacy in alleviating AngII-induced dysfunction in cardiomyocytes. The study suggests that MBT holds promise as a safe and effective prophylactic agent for cardiac hypertrophy, providing a deeper understanding of its mechanisms for cardioprotection against AngII-induced dysfunction.
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Cell death induction and protection by activation of ubiquitously expressed anion/cation channels. Part 3: the roles and properties of TRPM2 and TRPM7.
Yasunobu Okada, Tomohiro Numata, Ravshan Z Sabirov, Makiko Kashio, Peter G Merzlyak, Kaori Sato-Numata
Frontiers in cell and developmental biology 11 1246955 - 1246955 2023年
研究論文（学術雑誌）
Cell volume regulation (CVR) is a prerequisite for animal cells to survive and fulfill their functions. CVR dysfunction is essentially involved in the induction of cell death. In fact, sustained normotonic cell swelling and shrinkage are associated with necrosis and apoptosis, and thus called the necrotic volume increase (NVI) and the apoptotic volume decrease (AVD), respectively. Since a number of ubiquitously expressed ion channels are involved in the CVR processes, these volume-regulatory ion channels are also implicated in the NVI and AVD events. In Part 1 and Part 2 of this series of review articles, we described the roles of swelling-activated anion channels called VSOR or VRAC and acid-activated anion channels called ASOR or PAC in CVR and cell death processes. Here, Part 3 focuses on therein roles of Ca2+-permeable non-selective TRPM2 and TRPM7 cation channels activated by stress. First, we summarize their phenotypic properties and molecular structure. Second, we describe their roles in CVR. Since cell death induction is tightly coupled to dysfunction of CVR, third, we focus on their participation in the induction of or protection against cell death under oxidative, acidotoxic, excitotoxic, and ischemic conditions. In this regard, we pay attention to the sensitivity of TRPM2 and TRPM7 to a variety of stress as well as to their capability to physicall and functionally interact with other volume-related channels and membrane enzymes. Also, we summarize a large number of reports hitherto published in which TRPM2 and TRPM7 channels are shown to be involved in cell death associated with a variety of diseases or disorders, in some cases as double-edged swords. Lastly, we attempt to describe how TRPM2 and TRPM7 are organized in the ionic mechanisms leading to cell death induction and protection.
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Elucidation of the Role of Ion Channels in Cell Volume Regulation and Development of New Methods for Controlling Ion Channel Activity for Medical Applications
Numata Tomohiro
Akita J Med ( 秋田医学会 ) 49 ( 1 ) 1 - 9 2022年06月 [査読有り] [招待有り]
研究論文（学術雑誌） 単著
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ヒト心音図と心電図の測定に基づく中学校理科2学年2分野における「動物の体のつくりと働き」の授業 : ICSTシステムの適用
吉野 正巳, 勝木 知昭, 朝日 俊介, 沼田 朋大, 松川 正樹, 原田 和雄, 長谷川 正
東京学芸大学紀要. 自然科学系 ( 東京学芸大学教育実践研究推進本部 ) 75 63 - 75 2023年09月
論文(Article)
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Yamaguchi M.
Journal of Applied Polymer Science ( Journal of Applied Polymer Science ) 139 ( 8 ) 2022年02月
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心筋Sigma-1受容体を介したミトコンドリアCa<sup>2+</sup>シグナル調節機構
田頭 秀章, 篠田 康晴, 沼田 朋大, 福永 浩司
日本薬理学会年会要旨集 ( 公益社団法人 日本薬理学会 ) 96 1-B-P-020 2022年
Cardiovascular disease (CVD) is a leading cause of death worldwide. We previously reported that the Sigma-1 receptor (Sigmar1) is down-regulated in mice with cardiac dysfunction. Recent study suggested that Sigmar1 deficient mice display cardiac dysfunction via impairment of mitochondrial function. However, the mechanism of mitochondrial quality control mediated by Sigmar1 has not been investigated in detail. In this study, we investigated the role of Sigmar1 for ER-mitochondrial tethering and mitochondrial Ca<sup>2+</sup> signaling using a Sigmar1-knockdown cardiomyocytes. We found that disruption of ER-mitochondrial tethering and reduction of ER-mitochondrial Ca<sup>2+</sup> transport was induced by Sigmar1 knockdown in cardiomyocytes. We also demonstrated that Endothelin-1-induced cardiomyocyte hypertrophy is aggravated associated with induction of mitophagy in Sigmar1 knockdown cardiomyocytes. These data suggest that reduction of cardiac Sigmar1 is involved in myocyte hypertrophy by maintaining of intracellular Ca<sup>2+</sup> signaling mediated by regulation of ER-mitochondrial tethering.
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臓器特異的TRPM6/7機能抑制マウスを用いた新規病態モデル開発とその治療応用
基盤研究(C)
研究期間: 2022年04月 - 2025年03月 代表者: 田頭 秀章, 岩本 隆宏, 沼田 朋大
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分子間協働から創出される細胞容積調節能を利用した虚血性壊死からの救済策の開発
基盤研究(C)
研究期間: 2021年04月 - 2024年03月 代表者: 沼田 朋大
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動的エキシトンを利用した細胞膜機能の光制御
学術変革領域研究(A)
研究期間: 2020年11月 - 2025年03月 代表者: 村上 達也, 沼田 朋大