Abstract 111: Cdk5 is Associated in Cardiac Calcium Channelopathy

细胞周期蛋白依赖激酶5 高磷酸化 细胞生物学 MAPK/ERK通路 电压依赖性钙通道 激活剂(遗传学) 表型 激酶 钙通道 细胞周期蛋白依赖激酶 生物 化学 内科学 蛋白激酶A 医学 细胞周期 细胞凋亡 生物化学 基因 受体 细胞周期蛋白依赖激酶2
作者
Masayuki Yazawa,LouJin Song
出处
期刊:Circulation Research [Ovid Technologies (Wolters Kluwer)]
卷期号:119 (suppl_1)
标识
DOI:10.1161/res.119.suppl_1.111
摘要

Cardiac calcium channels play important roles in hearts. Mutations in Ca V 1.2 channels are associated with cardiac arrhythmias including long QT syndrome type 8 (LQTS8). Using human induced pluripotent stem cells (iPSCs) to generate human cardiomyocytes from LQTS8 patients, we reported that the G406R mutation (LQTS8, Timothy syndrome) affected channel inactivation, action potentials and calcium handling in human cardiomyocytes. We found that roscovitine, a cyclin-dependent kinase (CDK) inhibitor, rescued the phenotypes in LQTS8 cardiomyocytes. However, how roscovitine restores the physiological functions in the patient cardiomyocytes remains unclear. Our recent results using roscovitine analogs and CDK inhibitors suggested that CDK5 is involved in the molecular bases of LQTS8. We found that dominant negative forms and shRNA of CDK5 alleviated the phenotypes of the LQTS8 cardiomyocytes and that the expressions of phosphorylated ERK, EGR1 and CDK5R1, a CDK5 activator, significantly increased in the patient cardiomyocytes. The results reveal that calcium overload due to affected Ca V 1.2 inactivation activates ERK/EGR1 pathway, resulting in increased expression of CDK5R1. Biochemical assays supported a direct binding and phosphorylation of Ca V 1.2 channels by CDK5. Overall, the results demonstrated that CDK5 regulates Ca V 1.2 channels and that CDK5 inhibition could be a new therapeutic for LQTS8. This study demonstrates the role of ERK/EGR1/CDK5 in pathogenesis of cardiac arrhythmia. The outcomes of this study provide new insights into Ca V 1.2 channel regulation.

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