A sympathetic model of L-type Ca2+ channel-triggered arrhythmias
A sympathetic model of L-type Ca2+ channel-triggered arrhythmias
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DOI：
10.1152/ajpheart.01044.2009
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发表时间：
2010-01-01
影响因子：
4.8
通讯作者：
Kamp, Timothy J.
中科院分区：
文献类型：
--
作者：
Best, Jabe M.;Kamp, Timothy J.
L型钙通道在调节心肌细胞兴奋性和收缩性中起着关键作用。通过这些通道的Ca 2+内流[L型Ca 2+电流（伊卡，L）]有助于心室动作电位的平台期，并通过激活肌浆网中的Ca 2+释放通道或ryanodine受体启动兴奋-收缩偶联（1）。由此产生的Ca 2+诱导的Ca 2+释放导致细胞内Ca 2+瞬变，其激活肌丝。通过多种神经激素和第二信使途径（主要包括β-肾上腺素能受体（β-AR）/蛋白激酶A（PKA）信号通路）精确调节触发伊卡，L，部分控制了这种关键的细胞内Ca 2+瞬变（5）。L-型Ca 2+通道也可能是电不稳定性和血管生成的罪魁祸首。使用绵羊和犬浦肯野纤维进行的研究（其中应用了L型Ca 2+通道激活剂Bay K 8644）证明了伊卡，L在早期后除极（埃兹）启动中的重要性，特别是在缓慢起搏频率和较长动作电位持续时间（APD）时（4）。由于编码离子通道和相关蛋白的各种基因突变，以及获得性LQT综合征，伊卡，L的再激活与EAD形成有关，EAD形成可触发先天性长QT（LQT）综合征中危及生命的室性心律失常尖端扭转型室性心动过速（7）。此外，L-型Ca 2+通道的活性增加可导致心肌中的Ca 2+过载，这导致延迟后除极（DAD）的另一种形式的触发活动。例如，在犬楔块制备中，再次使用Bay K 8644药理学激活L型Ca 2+通道导致DAD并触发心律失常（8）。Timothy综合征（TS）是一种多系统疾病，其特征为ECG上QT间期延长、室性心律失常、综合征和自闭症，最近的描述再次表明L型Ca 2+通道参与了心肌梗死的发生。TS（LQT 8）由形成Cav 1的L型Ca 2+通道孔内的常染色体显性突变引起。2亚基，导致电压依赖性失活的显著损失（9，10）。动作电位建模研究直观地预测，维持伊卡，L将导致APD延长，与临床观察到的QT延长一致（10）。此外，预计伊卡，L的增加会导致DAD（9）。然而，临床上观察到的心律失常通常发生在交感神经张力增加的情况下，例如哭泣，因此β-AR信号传导对TS心脏表型的影响是重要的。
L-TYPE CA 2+ CHANNELS PLAY a pivotal role in regulating cellular excitability and contractility in cardiac tissue. Ca2+ influx through these channels [L-type Ca2+ current (ICa, L)] contributes to the plateau phase of the ventricular action potential and initiates excitation-contraction coupling by activating Ca2+-release channels or ryanodine receptors in the sarcoplasmic reticulum (1). The resulting Ca2+-induced Ca2+ release leads to the intracellular Ca2+ transient, which activates the myofilaments. Control of this critical intracellular Ca2+ transient is afforded, in part, by the precise regulation of the triggering ICa, L by a variety of neurohormonal and second-messenger pathways, including prominently the β-adrenergic receptor (β-AR)/protein kinase A (PKA) signaling pathway (5). L-type Ca2+ channels can also be the culprit in electrical instability and arrhythmogenesis. Studies using sheep and canine Purkinje fibers, in which the L-type Ca2+ channel activator Bay K 8644 was applied, demonstrated the importance of ICa, L in the initiation of early afterdepolarizations (EADs), particularly at slow pacing frequencies and with longer action potential durations (APD)(4). Reactivation of ICa, L has been implicated in EAD formation that can trigger the life-threatening ventricular arrhythmia torsades de pointes in congenital long QT (LQT) syndromes due to mutations in a variety of genes encoding ion channels and associated proteins, as well as in acquired LQT syndrome (7). Furthermore, increased activity of L-type Ca2+ channels may lead to Ca2+ overload in cardiac muscle, which results in another form of triggered activity from delayed afterdepolarizations (DADs). For example, in canine wedge preparations, pharmacological activation of L-type Ca2+ channels again using Bay K 8644 resulted in DADs and triggered arrhythmias (8). The recent description of Timothy syndrome (TS), a multisystem disorder characterized by prolonged QT interval on ECG, ventricular arrhythmias, syndactly, and autism, has again implicated L-type Ca2+ channels in arrhythmogenesis. TS (LQT8) arises from autosomal dominant mutations within the L-type Ca2+ channel pore forming Cav1. 2 subunit that lead to a marked loss of voltage-dependent inactivation (9, 10). Action potential modeling studies intuitively predicted that the maintained ICa, L would result in APD prolongation, consistent with the clinically observed QT prolongation (10). Furthermore, the increase in ICa, L was predicted to lead to DADs (9). However, the clinically observed arrhythmias typically occur in the setting of increased sympathetic tone, such as crying, and so the impact of β-AR signaling on the TS cardiac phenotype is of importance.