Increased coupled gating of L-type Ca2+ channels during hypertension and Timothy syndrome.
Increased coupled gating of L-type Ca2+ channels during hypertension and Timothy syndrome.
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DOI：
10.1161/circresaha.109.213363
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发表时间：
2010-03-05
影响因子：
20.1
通讯作者：
Santana LF
中科院分区：
文献类型：
--
作者：
Navedo MF;Cheng EP;Yuan C;Votaw S;Molkentin JD;Scott JD;Santana LF
L 型 (Cav1.2) Ca2+ 通道是肌肉和神经功能的关键调节因子。尽管 Cav1.2 通道活性因地区而异，但人们对这种异质性背后的机制知之甚少。检验 Cav1.2 通道可以协调选通的假设。我们使用光学和电生理学方法记录表达 Cav1.2 通道的心脏、平滑肌和 tsA-201 细胞中的 Cav1.2 通道活性。与我们的假设一致，我们发现 Cav1.2 通道的小簇可以串联打开和关闭。 FRET 和电生理学研究表明，Cav1.2 通道的这种耦合涉及相邻通道之间通过其 C 末端的瞬时相互作用。在高血压平滑肌和表达突变型 Cav1.2 通道的细胞中，耦合门控事件的频率增加，该通道会导致蒂莫西综合征 (LQT8) 患者出现心律失常和自闭症。 Cav1.2通道的耦合门控可能代表了在生理和病理条件下调节神经元、心脏和动脉平滑肌的Ca2+流入和兴奋性的新机制。
L-type (Cav1.2) Ca2+ channels are critical regulators of muscle and neural function. Although Cav1.2 channel activity varies regionally, little is known about the mechanisms underlying this heterogeneity. To test the hypothesis that Cav1.2 channels can gate coordinately. We used optical and electrophysiological approaches to record Cav1.2 channel activity in cardiac, smooth muscle, and tsA-201 cells expressing Cav1.2 channels. Consistent with our hypothesis, we found that small clusters of Cav1.2 channels can open and close in tandem. FRET and electrophysiological studies suggest that this coupling of Cav1.2 channels involves transient interactions between neighboring channels via their C-termini. The frequency of coupled gating events increases in hypertensive smooth muscle and in cells expressing a mutant Cav1.2 channel that causes arrhythmias and autism in humans with Timothy syndrome (LQT8). Coupled gating of Cav1.2 channels may represent a novel mechanism for the regulation of Ca2+ influx and excitability in neurons, cardiac, and arterial smooth muscle under physiological and pathological conditions.