Molecular basis for cardiac muscle diseases caused by functional abnormalities of Z-disc

Z盘功能异常引起的心肌疾病的分子基础

• 批准号: 23659414
• 负责人: KIMURA Akinori
• 金额: $ 2.41万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Challenging Exploratory Research
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23659414/
• 关键词: 遺伝学; 遺伝子; ゲノム; 循環器・高血圧; Ｚ帯; 循環器疾患; 心筋症; 不整脈; 遺伝子変異; SLMAP; ZASP; 細胞内輸送障害; Z帯; 機能連関; Naチャネル; ストレス反応; ストレッチ反応

In this study, we investigated functional role of Z-disc in the molecular pathogenesis of cardiomyopathy and arrhythmia to develop a novel strategy for the diseases via modifying the Z-disc function. It was deciphered that mutations in ZASP caused cardiomyopathy accompanied by ventricular arrhythmia via impairing the function of INa through affecting expression of cardiac sodium channel Nav1.5. In addition, we revealed that the mutations in SLMAP gene encoding for a Z-disc protein of unknown function. It was found that SLMAP mutations impaired INa function via inhibiting intracellular trafficking of Nav1.5. Moreover, we also revealed that a SCN3B mutation inhibited intracellular trafficking of Nav1.5 and affected INa function. These observations have indicated that the intracellular trafficking of Nav1.5 is in part controlled by Z-disc elements. On the other hand, we found that a heart-specific small subunit of myosin phosphatase, M21, localized at Z-disc and increased the phosphorylation of a large subunit of myosin phosphatase, M110, which resulted in increased calcium sensitivity of cardiac muscle contraction. Inhibition of binding between M21 and M110 suppressed the phosphorylation of M110. M21 also bound to a Rho-kinase and enhanced its kinase activity, suggesting that inhibition of rho-kinase would be useful in modulation of calcium sensitivity of cardiac muscle contraction.

在本研究中，我们研究了Z-disc在心肌病和心律失常分子发病机制中的功能作用，以期通过改变Z-disc的功能来开发治疗这些疾病的新策略。ZASP基因突变可能通过影响心脏钠通道Nav1.5的表达，损害INa的功能，从而导致心肌病伴室性心律失常。此外，我们还发现SLMAP基因突变编码一种功能未知的Z盘蛋白。发现SLMAP突变通过抑制Nav1.5的细胞内运输而损害INa功能。此外，我们还揭示了SCN 3B突变抑制Nav1.5的细胞内运输并影响INa功能。这些观察结果表明，Nav1.5的细胞内运输部分由Z盘元件控制。另一方面，我们发现心肌特异性肌球蛋白磷酸酶的小亚基M21定位于Z盘，并增加肌球蛋白磷酸酶的大亚基M110的磷酸化，从而导致心肌收缩的钙敏感性增加。抑制M21和M110之间的结合抑制了M110的磷酸化。M21还与Rho激酶结合并增强其激酶活性，这表明抑制Rho激酶可用于调节心肌收缩的钙敏感性。

项目成果

心筋症の遺伝子異常と分子病態

心肌病的遗传异常和分子病理学

• 发表时间: 2011
• 作者: Arimura T;Kimura A;木村彰方
• 通讯作者: 木村彰方

Loss of function of hNav1.5 by a ZASP1 mutation associated with intraventricular conduction disturbances in left ventricular noncompaction.

• DOI: 10.1161/circep.111.969220
• 发表时间: 2012-10
• 期刊: Circulation. Arrhythmia and electrophysiology
• 作者: Xi Y;Ai T;De Lange E;Li Z;Wu G;Brunelli L;Kyle WB;Turker I;Cheng J;Ackerman MJ;Kimura A;Weiss JN;Qu Z;Kim JJ;Faulkner G;Vatta M
• 通讯作者: Vatta M

ブルガダ症候群患者に見出されたSLMAP変異とその機能解析

Brugada综合征患者SLMAP突变及其功能分析

• 发表时间: 2012
• 作者: Watanabe H;Nogami A;Ohkubo K;Kawata H;Hayashi Y;Ishikawa T;Makiyama T;Nagao S;Yagihara N;Takehara N;Kawamura Y;Sato A;Okamura K;Hosaka Y;Sato M;Fukae S;Chinushi M;Oda H;Okabe M;Kimura A;Maemura K;Watanabe I;Kamakura S;Horie M;Aizaw;Minamino T.;有村卓朗,石川泰輔,木村彰方;Minamino T.;Minamino T.;石川泰輔,佐藤光希,有村卓朗,蒔田直昌,木村彰方
• 通讯作者: 石川泰輔,佐藤光希,有村卓朗,蒔田直昌,木村彰方

心筋症:遺伝子異常からみた分子病態

心肌病：从遗传异常看出分子病理学

• 发表时间: 2011
• 作者: Shiota A;Shimabukuro M;Fukuda D;Soeki T;Sato H;Uematsu E;Hirata Y;Kurobe H;Maeda N;Sakaue H;Masuzaki H;Shimomura I;Sata M.;Egashira K;木村彰方
• 通讯作者: 木村彰方

Heart-specific Small Subunit of Myosin Light Chain Phosphatase Activates Rho-associated Kinase and Regulates Phosphorylation of Myosin Phosphatase Target Subunit 1

• DOI: 10.1074/jbc.m110.122390
• 发表时间: 2010-10-29
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Shichi, Daisuke;Arimura, Takuro;Kimura, Akinori
• 通讯作者: Kimura, Akinori