Investigation of cardiac ion channel modulation in mouse models

人KCNQ 1和HERG基因编码电压门控钾通道的<$-亚基，分别介导IKs和IKr-。这些电流是心室动作电位复极的主要决定因素。KCNQ 1和HERG的突变与心电图QT间期异常延长有关，即长QT综合征（LQTS）。在LQTS患者中，身体和情绪压力通常会导致危及生命的室性心动过速发作，具有猝死的高风险。将突变IKr或IKs通道表达与室性心律失常的发作性发生联系起来的触发因素的分子基础尚不清楚。我们推测，室性心律失常可能最终发生，因为突变IKr或IKs通道不能正确响应肾上腺素能信号通路在心室肌细胞。具体来说，我们计划在表达LQT突变体的转基因小鼠品系中测试这一假设，该突变体在异源表达系统中产生功能通道，但对肾上腺素能信号通路不敏感。此外，我们想调查的重要性，多蛋白信号复合物的时空调节心脏IKs和/或IKr通道活性。这些结果有望进一步加深我们对肾上腺素能信号通路对IKs和/或IKr通道活性的动态调节及其病理生理后果的理解。

Human KCNQ1 and HERG genes encode ¿-subunits of voltage-gated potassium-channels that mediate IKs and, respectively, IKr-. The currents are major determinants of ventricular action potential repolarization. Mutations in KCNQ1 and HERG are associated with an abnormally prolonged electrocardiographic QT interval, the long QT syndrome (LQTS). Physical and emotional stress often precipitates in LQTS patients life threatening episodes of ventricular tachycardias with a high risk of sudden death. The molecular basis of the trigger which connects mutant IKr or IKs channel expression to episodic occurrence of ventricular arrhythmia, is not clear. We hypothesize that a ventricular arrhythmia may eventually occur because mutant IKr or IKs channels do not properly respond to adrenergic signaling pathways in ventricular myocytes. Specifically, we plan to test this hypothesis in transgenic mouse lines that express LQT mutants which produce in heterologous expression systems functional channels, but are insensitive to adrenergic signaling pathways. Furthermore, we want to investigate the importance of multiprotein signaling complexes for spatiotemporal regulation of cardiac IKs and/or IKr channel activity. The results are expected to further our understanding of dynamic regulation of IKs and/or IKr channel activity by adrenergic signaling pathways and its pathophysiological consequences.