Hypoxic modulation of cardiac L-type Ca2+ current: interaction of reactive oxygen species and beta-adrenergic signaling.
Hypoxic modulation of cardiac L-type Ca2+ current: interaction of reactive oxygen species and beta-adrenergic signaling.
复制标题
心脏 L 型 Ca2 电流的缺氧调节：活性氧和 β-肾上腺素能信号传导的相互作用。
DOI：
10.1016/j.cardiores.2005.06.010
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发表时间：
2005
影响因子：
10.8
通讯作者：
Mallet,RobertT
中科院分区：
文献类型：
--
作者：
Mallet,RobertT
肌层l型Ca2+通道是心肌细胞兴奋-收缩耦合机制的组成部分。膜去极化至À30 mv0打开这些通道，允许Ca2+快速流入，在2 - 3 ms内达到峰值。这种向内的Ca2+电流（ICa）产生心肌细胞动作电位的平台期，并通过排列在l型通道附近的红嘌呤敏感Ca2+通道，触发肌浆网大量释放Ca2+。由此产生的细胞质Ca2+瞬态激活了过桥循环和收缩机械产生的机械力，并使l型Ca2+电流[2]失活。心脏l型通道包含四个亚基（a1C, a2, h2, y）[1,2]。大a1C亚基的四个同源结构域中的每一个都包含六个跨膜的螺旋；四个a1C结构域中的螺旋5和6结合形成Ca2+孔[2]。l型Ca2+电流受蛋白激酶的生理调节，这些蛋白激酶共价修饰a1C亚基以调节固有的通道门控特性。h-肾上腺素能活性通过蛋白激酶A磷酸化a1C[2]的Ser-1928来增加ICa。1)，将通道的门控行为从模式0（很少或从不打开）转变为模式1（低打开概率，通道只短暂打开）和模式2（高打开概率，通道打开时间延长）[1,3]。这一机制对h-肾上腺素能增强心肌收缩性能有重要作用。蛋白激酶C可能磷酸化糖化血红蛋白氨基末端附近的Thr-27和/或Thr-31，从而导致ICa[1]的单相降低或短暂升高，随后降低。由一氧化氮/鸟苷酸环化酶/环GMP级联激活的蛋白激酶G对ICa具有复杂的作用：该激酶直接磷酸化l型通道激活ICa，但该激酶也通过激活蛋白磷酸酶（使a1C的ser-1928去磷酸化）和磷酸二酯酶2（降解环AMP[1]）来抑制ICa的h-肾上腺素能激活[2,4]。
Sarcolemmal L-type Ca2+ channels are integral components of the excitation–contraction coupling mechanism in cardiomyocytes. Membrane depolarization to À30 mVopens these channels [1], allowing rapid influx of Ca2+ which peaks within 2–3 ms [2]. This inward Ca2+ current (ICa) produces the plateau phase of the cardiomyocyte action potential and triggers a massive release of Ca2+ from the sarcoplasmic reticulum via ryanodine-sensitive Ca2+ channels, arrayed in close proximity to the L-type channels. The resultant cytosolic Ca2+ transient activates crossbridge cycling and mechanical force production by the contractile machinery and inactivates the L-type Ca2+ current [2]. Cardiac L-type channels contain four subunits (a1C, a2, h2, y)[1, 2]. Each of the four homologous domains of the large a1C subunit harbor six membrane-spanning a helices; helices 5 and 6 of the four a1C domains combine to form a Ca2+ pore [2]. L-type Ca2+ current is physiologically regulated by protein kinases that covalently modify the a1C subunit to modulate intrinsic channel gating properties. h-Adrenergic activity increases ICa via protein kinase A phosphorylation of Ser-1928 of a1C [2](Fig. 1), which shifts gating behavior of the channels from mode 0 (rarely or never open) to modes 1 (low open probability; channels open only briefly) and 2 (high open probability; prolonged opening of channels)[1, 3]. This mechanism contributes importantly to h-adrenergic enhancement of myocardial contractile performance. Protein kinase C may phosphorylate Thr-27 and/or Thr-31 near the amino terminus of a1C, producing either a monophasic decrease or a transient increase followed by a decrease in ICa [1].Protein kinase G, activated by the nitric oxide/guanylate cyclase/cyclic GMP cascade, exerts complex effects on ICa: direct phosphorylation of the L-type channel by this kinase activates ICa, but the kinase also suppresses h-adrenergic activation of ICa [2, 4] by activating protein phosphatase, which dephosphorylates ser-1928 of a1C, and phosphodiesterase 2, which degrades cyclic AMP [1].