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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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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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Yasunobu Okada, Ravshan Z. Sabirov, Petr G. Merzlyak, Tomohiro Numata and Kaori Sato-Numata
Frontiers in Physiology ( Frontiers in Physiology ) 12 805148 - 805148 2021年12月 [査読有り]
研究論文（学術雑誌） 国際共著
Molecular identification was, at last, successfully accomplished for three types of anion channels that are all implicated in cell volume regulation/dysregulation. LRRC8A plus LRRC8C/D/E, SLCO2A1, and TMEM206 were shown to be the core or pore-forming molecules of the volume-sensitive outwardly rectifying anion channel (VSOR) also called the volume-regulated anion channel (VRAC), the large-conductance maxi-anion channel (Maxi-Cl), and the acid-sensitive outwardly rectifying anion channel (ASOR) also called the proton-activated anion channel (PAC) in 2014, 2017, and 2019, respectively. More recently in 2020 and 2021, we have identified the S100A10-annexin A2 complex and TRPM7 as the regulatory proteins for Maxi-Cl and VSOR/VRAC, respectively. In this review article, we summarize their biophysical and structural properties as well as their physiological roles by comparing with each other on the basis of their molecular insights. We also point out unsolved important issues to be elucidated soon in the future.
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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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二つのタンパク質の協力で細胞の大きさを一定に保つメカニズムを解明
沼田 朋大, 岡田 泰伸
日本生理学雑誌 ( (一社)日本生理学会 ) 83 ( 3 ) 49 - 50 2021年08月
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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