The voltage-dependent L-type Ca2+ (CaV1.2) channel C-terminus fragment is a bi-modal vasodilator
The voltage-dependent L-type Ca2+ (CaV1.2) channel C-terminus fragment is a bi-modal vasodilator
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DOI：
10.1113/jphysiol.2013.251926
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发表时间：
2013-06-01
影响因子：
5.5
通讯作者：
Jaggar, Jonathan H.
中科院分区：
文献类型：
--
作者：
Bannister, John P.;Leo, Marie Dennis;Jaggar, Jonathan H.
要点中心点电压依赖性 L 型 Ca2+ (CaV1.2) 通道是主要的 Ca2+ 流入途径，并且是动脉平滑肌细胞收缩性调节的核心。中心点 CaV1.2 作为全长通道存在，并在大鼠和人动脉平滑肌细胞中裂解为短 CaV1.2 和 C 末端 (CCt) 片段。中心点 CCt 降低 CaV1.2 转录，并将电流激活和失活的电压依赖性转变为动脉平滑肌细胞中更去极化的电位。中心点 CCt 减少压力和去极化引起的血管收缩。中心点 CCt 是一种双模式血管扩张剂。摘要 电压依赖性 L 型 Ca2+ 通道 (CaV1.2) 是血管平滑肌细胞（肌细胞）中主要的 Ca2+ 进入途径。 CaV1.2 通道控制全身血压和器官血流，并在血管疾病中发生病理改变，从而改变血管收缩力。 CaV1.2 远端 C 末端容易受到蛋白水解切割，从而产生截短的 CaV1.2 亚基和切割的 C 末端片段 (CCt)。先前对心肌细胞和神经元的研究已确定 CCt 既是转录因子又是 CaV1.2 通道抑制剂，其中一些效应的基础是不同的信号传导机制。动脉肌细胞中 CCt 的存在和生理功能尚不清楚，但考虑到 CaV1.2 通道的功能意义，研究很重要。在这里，我们发现 CCt 存在于大鼠和人类阻力大小的脑动脉的肌细胞中，它位于细胞核和质膜上。动脉肌细胞中的重组 CCt 表达抑制 CaV1.2 转录并减少 CaV1.2 蛋白。 CCt 诱导 CaV1.2 电流激活和失活的电压依赖性发生去极化转变，并减少肌细胞中的非失活电流。缺乏假定的核定位序列 (92CCt) 的重组截短 CCt 不会定位到细胞核，并且对动脉 CaV1.2 转录或蛋白质没有影响。然而，与 CCt 类似，92CCt 改变了 CaV1.2 激活和失活的电压依赖性。 CCt 和 92CCt 均抑制压力和去极化诱导的血管收缩，尽管 CCt 是更有效的血管扩张剂。这些数据表明内源性 CCt 存在并降低动脉肌细胞中的 CaV1.2 通道表达和电压敏感性。因此，CCt 是一种双模式血管扩张剂。
Key points center dot Voltage-dependent L-type Ca2+ (CaV1.2) channels are the major Ca2+ influx pathway and are central to contractility regulation in arterial smooth muscle cells. center dot CaV1.2 exists as a full-length channel and undergoes cleavage to a short CaV1.2 and a C-terminus (CCt) fragment in rat and human arterial smooth muscle cells. center dot CCt decreases CaV1.2 transcription and shifts the voltage dependence of current activation and inactivation to more depolarized potentials in arterial smooth muscle cells. center dot CCt reduces pressure- and depolarization-induced vasoconstriction. center dot CCt is a bi-modal vasodilator. Abstract Voltage-dependent L-type Ca2+ channels (CaV1.2) are the primary Ca2+ entry pathway in vascular smooth muscle cells (myocytes). CaV1.2 channels control systemic blood pressure and organ blood flow and are pathologically altered in vascular diseases, which modifies vessel contractility. The CaV1.2 distal C-terminus is susceptible to proteolytic cleavage, which yields a truncated CaV1.2 subunit and a cleaved C-terminal fragment (CCt). Previous studies in cardiac myocytes and neurons have identified CCt as both a transcription factor and CaV1.2 channel inhibitor, with different signalling mechanisms proposed to underlie some of these effects. CCt existence and physiological functions in arterial myocytes are unclear, but important to study given the functional significance of CaV1.2 channels. Here, we show that CCt exists in myocytes of both rat and human resistance-size cerebral arteries, where it locates to both the nucleus and plasma membrane. Recombinant CCt expression in arterial myocytes inhibited CaV1.2 transcription and reduced CaV1.2 protein. CCt induced a depolarizing shift in the voltage dependence of both CaV1.2 current activation and inactivation, and reduced non-inactivating current in myocytes. Recombinant truncated CCt lacking a putative nuclear localization sequence (92CCt) did not locate to the nucleus and had no effect on arterial CaV1.2 transcription or protein. However, 92CCt shifted the voltage dependence of CaV1.2 activation and inactivation similarly to CCt. CCt and 92CCt both inhibited pressure- and depolarization-induced vasoconstriction, although CCt was a far more effective vasodilator. These data demonstrate that endogenous CCt exists and reduces both CaV1.2 channel expression and voltage sensitivity in arterial myocytes. Thus, CCt is a bi-modal vasodilator.