Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome.
Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome.
复制标题
DOI：
10.1016/j.stemcr.2017.05.028
复制
发表时间：
2017-07-11
影响因子：
5.9
通讯作者：
Yazawa M
中科院分区：
文献类型：
--
作者：
Song L;Park SE;Isseroff Y;Morikawa K;Yazawa M
L型钙通道CaV1.2在心脏功能中起着重要作用。据报道，CaV1.2中的功能获得性突变与蒂莫西综合征相关，蒂莫西综合征是一种以QT延长和并指为特征的疾病。以前我们证明，roscovitine，细胞周期蛋白依赖性激酶（CDK）抑制剂，可以拯救诱导多能干细胞衍生的心肌细胞从蒂莫西综合征患者的表型。然而，roscovitine究竟是如何拯救这些表型的仍不清楚。在这里，我们报告了一个潜在的机制Roscovitine对蒂莫西综合征心肌细胞的治疗作用。我们使用roscovitine类似物和CDK抑制剂和构建体的结果表明，roscovitine部分地通过抑制CDK 5而表现出其治疗效果。这项研究的结果使我们能够确定CaV1.2通道受CDK5调节的分子机制。这项研究为Timothy综合征患者的心脏钙通道调节和未来治疗方法的发展提供了见解。CDK5抑制剂可使Timothy综合征心肌细胞的表型发生变化CDK5可调节心肌细胞中CaV1.2通道的功能Yazawa及其同事报道了细胞周期蛋白依赖性激酶5（CDK5）作为心肌细胞中CaV1.2通道的调节剂和Timothy综合征的分子治疗靶点。这项研究为Timothy综合征患者的心脏钙通道调节和未来治疗方法的发展提供了见解。
L-type calcium channel CaV1.2 plays an essential role in cardiac function. The gain-of-function mutations in CaV1.2 have been reported to be associated with Timothy syndrome, a disease characterized by QT prolongation and syndactyly. Previously we demonstrated that roscovitine, a cyclin-dependent kinase (CDK) inhibitor, could rescue the phenotypes in induced pluripotent stem cell-derived cardiomyocytes from Timothy syndrome patients. However, exactly how roscovitine rescued the phenotypes remained unclear. Here we report a mechanism potentially underlying the therapeutic effects of roscovitine on Timothy syndrome cardiomyocytes. Our results using roscovitine analogs and CDK inhibitors and constructs demonstrated that roscovitine exhibits its therapeutic effects in part by inhibiting CDK5. The outcomes of this study allowed us to identify a molecular mechanism whereby CaV1.2 channels are regulated by CDK5. This study provides insights into the regulation of cardiac calcium channels and the development of future therapeutics for Timothy syndrome patients. CDK5 Inhibition alleviates the phenotypes in Timothy syndrome cardiomyocytes CDK5 regulates the functions of CaV1.2 channels in cardiomyocytes Yazawa and colleagues report cyclin-dependent kinase 5 (CDK5) as a regulator of CaV1.2 channels in cardiomyocytes and a molecular therapeutic target for Timothy syndrome. This study provides insights into the regulation of cardiac calcium channels and the development of future therapeutics for Timothy syndrome patients.
登录
查看更多内容
DOI：
10.1111/j.1432-1033.1997.t01-2-00527.x
发表时间：
1997-01-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Meijer, L;Borgne, A;Moulinoux, JP
通讯作者：
Moulinoux, JP
影响因子：
64.8
作者：
Itzhaki, Ilanit;Maizels, Leonid;Gepstein, Lior
通讯作者：
Gepstein, Lior
影响因子：
3.7
作者：
Hennessey JA;Boczek NJ;Jiang YH;Miller JD;Patrick W;Pfeiffer R;Sutphin BS;Tester DJ;Barajas-Martinez H;Ackerman MJ;Antzelevitch C;Kanter R;Pitt GS
通讯作者：
Pitt GS
DOI：
10.1111/j.1540-8159.2010.02913.x
发表时间：
2012-03-01
影响因子：
1.8
作者：
Shah, Dipak P.;Baez-Escudero, Jose L.;Burke, Martin C.
通讯作者：
Burke, Martin C.
影响因子：
3.5
作者：
Brasca, Maria Gabriella;Albanese, Clara;Ciomei, Marina
通讯作者：
Ciomei, Marina