A coupled SYSTEM of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart's pacemaker.
A coupled SYSTEM of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart's pacemaker.
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DOI：
10.1161/circresaha.109.206078
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发表时间：
2010-03-05
影响因子：
20.1
通讯作者：
Vinogradova TM
中科院分区：
文献类型：
--
作者：
Lakatta EG;Maltsev VA;Vinogradova TM
窦房结起搏细胞 (SANC) 表面膜上的离子通道是动作电位的近端原因。每个单独的通道类型都在电压钳下得到了彻底的表征，并且在计算机中重建的离子通道电流的整体产生了有节奏的动作电位。因此，这个整体可以被设想为一个表面“膜时钟”（M时钟）。局部肌膜下 Ca2+ 释放是在舒张末期去极化期间由肌浆网通过兰尼碱受体产生的，被称为细胞内“Ca2+ 时钟”，因为它们的自发发生在电压钳期间或在去污剂透化的 SANC 中以及在计算机中也是周期性的。在自发激发的 SANC 中，M 时钟和 Ca2+ 时钟不是孤立运行的，而是通过膜电压、肌膜下 Ca2+ 以及 PKA 和 CaMKII 依赖性蛋白磷酸化调节的多种相互作用共同工作。通过这些相互作用，两个子系统时钟相互带动，形成一个强大、稳定、耦合的时钟系统，驱动正常的心脏起搏器细胞自动化。 G 蛋白偶联受体信号传导可产生起搏器灵活性，即通过影响调节稳健的基础偶联时钟系统功能的这些相同因素，影响节律性动作电位放电率的变化。本综述检查了构成心脏 SANC 中耦合时钟系统概念基础的证据。
Ion channels on the surface membrane of sinoatrial nodal pacemaker cells (SANC) are the proximal cause of an action potential. Each individual channel type has been thoroughly characterized under voltage clamp, and the ensemble of the ion channel currents reconstructed in silico generates rhythmic action potentials. Thus, this ensemble can be envisioned as a surface “membrane clock” (M clock). Localized subsarcolemmal Ca2+ releases are generated by the sarcoplasmic reticulum via ryanodine receptors during late diastolic depolarization and are referred to as an intracellular “Ca2+ clock”, because their spontaneous occurrence is periodic during voltage clamp or in detergent-permeabilized SANC, and in silico as well. In spontaneously firing SANC, the M and Ca2+ clocks do not operate in isolation, but work together via numerous interactions modulated by membrane voltage, subsarcolemmal Ca2+, and PKA and CaMKII-dependent protein phosphorylation. Through these interactions the two subsystem clocks become mutually entrained to form a robust, stable, coupled-clock system that drives normal cardiac pacemaker cell automaticity. G-protein coupled-receptors signaling creates pacemaker flexibility, i.e. effects changes in the rhythmic action potential firing rate, by impacting on these very same factors that regulate robust basal coupled-clock system function. This review examines evidence that forms the basis of this coupled-clock system concept in cardiac SANC.