Voltage-Gated Sodium Channel Phosphorylation at Ser571 Regulates Late Current, Arrhythmia, and Cardiac Function In Vivo.
Voltage-Gated Sodium Channel Phosphorylation at Ser571 Regulates Late Current, Arrhythmia, and Cardiac Function In Vivo.
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DOI：
10.1161/circulationaha.114.015218
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发表时间：
2015-08-18
期刊：
影响因子：
37.8
通讯作者：
Hund TJ
中科院分区：
文献类型：
--
作者：
Glynn P;Musa H;Wu X;Unudurthi SD;Little S;Qian L;Wright PJ;Radwanski PB;Gyorke S;Mohler PJ;Hund TJ
电压门控Na+通道（Nav）是心肌细胞膜兴奋性和心脏功能所必需的。Nav电流（INa）是一种大幅度、短持续时间的“尖峰”，由快速通道激活随后立即失活产生。然而，即使在正常条件下，由于通道亚群的不完全/失败失活，INa的小的“晚期”组分（INa，L）仍然存在。值得注意的是，INa，L与先天性和获得性疾病状态直接相关。多功能Ca ~（2+）/钙调素依赖性激酶Ⅱ（CaMK Ⅱ）已被鉴定为疾病中INa，L的重要激活剂。已经发现了几个潜在的CaMKII磷酸化位点，包括Nav1.5 DI-DII接头中的Ser 571，但体内INa，L的CaMKII依赖性调节的分子机制仍然未知。为了确定Ser 571的体内作用，产生了两种Scn 5a敲入小鼠模型，其表达：1）在Ser 571处具有磷酸化模拟突变的Nav1.5（S571 E），或2）磷酸化位点消融的Nav1.5（S571 A）。电生理学研究表明，Ser 571调节INa，L，但不是以前与CaMKII相关的其他通道特性。Ser 571介导的INa，L增加促进异常复极和细胞内Ca 2+处理，并在细胞和动物水平上增加对心律失常的易感性。重要的是，Ser 571是压力超负荷引起的适应不良重构和心律失常所必需的。我们的数据提供了第一个在体内证据的分子机制CaMKII激活的致病性INa，L。与改进潜在疗法的合理设计相关，我们的研究结果表明，Nav1.5的Ser 571依赖性调节特异性调节INa，L，而不改变电流的关键生理成分。
Voltage-gated Na+ channels (Nav) are essential for myocyte membrane excitability and cardiac function. Nav current (INa) is a large amplitude, short duration “spike” generated by rapid channel activation followed immediately by inactivation. However, even under normal conditions, a small “late” component of INa (INa,L) persists due to incomplete/failed inactivation of a subpopulation of channels. Notably, INa,L is directly linked with both congenital and acquired disease states. The multifunctional Ca2+/calmodulin-dependent kinase II (CaMKII) has been identified as an important activator of INa,L in disease. Several potential CaMKII phosphorylation sites have been discovered, including Ser571 in the Nav1.5 DI-DII linker, but the molecular mechanism underlying CaMKII-dependent regulation of INa,L in vivo remains unknown. To determine the in vivo role of Ser571, two Scn5a knock-in mouse models were generated expressing either: 1) Nav1.5 with a phosphomimetic mutation at Ser571 (S571E), or 2) Nav1.5 with the phosphorylation site ablated (S571A). Electrophysiology studies revealed that Ser571 regulates INa,L but not other channel properties previously linked to CaMKII. Ser571-mediated increases in INa,L promote abnormal repolarization and intracellular Ca2+ handling, and increase susceptibility to arrhythmia at the cellular and animal level. Importantly, Ser571 is required for maladaptive remodeling and arrhythmias in response to pressure overload. Our data provide the first in vivo evidence for the molecular mechanism underlying CaMKII activation of the pathogenic INa,L. Relevant for improved rational design of potential therapies, our findings demonstrate that Ser571-dependent regulation of Nav1.5 specifically tunes INa,L without altering critical physiological components of the current.