Lakatta Edward G, Vinogradova Tatiana M, Maltsev Victor A
National Institutes of Health, National Institute on Aging, Laboratory of Cardiovascular Science, Baltimore, MD 21224, USA.
Ann N Y Acad Sci. 2008 Mar;1123:41-57. doi: 10.1196/annals.1420.006.
Earlier studies of the initiating event of normal automaticity of the heart's pacemaker cells, inspired by classical quantitative membrane theory, focused upon ion currents (IK, I f) that determine the maximum diastolic potential and the early phase of the spontaneous diastolic depolarization (DD). These early DD events are caused by the prior action potential (AP) and essentially reflect a membrane recovery process. Events following the recovery process that ignite APs have not been recognized and remained a mystery until recently. These critical events are linked to rhythmic intracellular signals initiated by Ca2+ clock (i.e., sarcoplasmic reticulum [SR] cycling Ca2+). Sinoatrial cells, regardless of size, exhibit intense ryanodine receptor (RyR), Na+/Ca2+ exchange (NCX)-1, and SR Ca2+ ATPase-2 immunolabeling and dense submembrane NCX/RyR colocalization; Ca2+ clocks generate spontaneous stochastic but roughly periodic local subsarcolemmal Ca2+ releases (LCR). LCRs generate inward currents via NCX that exponentially accelerate the late DD. The timing and amplitude of LCR/I NCX-coupled events control the timing and amplitude of the nonlinear terminal DD and therefore ultimately control the chronotropic state by determining the timing of the I CaL activation that initiates the next AP. LCR period is precisely controlled by the kinetics of SR Ca2+ cycling, which, in turn, are regulated by 1) the status of protein kinase A-dependent phosphorylation of SR Ca2+ cycling proteins; and 2) membrane ion channels ensuring the Ca2+ homeostasis and therefore the Ca2+ available to Ca2+ clock. Thus, the link between early DD and next AP, missed in earlier studies, is ensured by a precisely physiologically regulated Ca2+ clock within pacemaker cells that integrates multiple Ca2+-dependent functions and rhythmically ignites APs during late DD via LCRs-I NCX coupling.
受经典定量膜理论启发，早期关于心脏起搏细胞正常自律性起始事件的研究聚焦于决定最大舒张电位和自发性舒张期去极化（DD）早期阶段的离子电流（IK、If）。这些早期的DD事件由先前的动作电位（AP）引起，本质上反映了膜恢复过程。直到最近，恢复过程之后引发AP的事件才被认识到，仍然是个谜。这些关键事件与由Ca2+时钟（即肌浆网[SR]循环Ca2+）引发的节律性细胞内信号有关。无论大小，窦房结细胞均表现出强烈的兰尼碱受体（RyR）、钠钙交换体（NCX）-1和SR Ca2+ATP酶-2免疫标记以及致密的膜下NCX/RyR共定位；Ca2+时钟产生自发的随机但大致周期性的局部肌膜下Ca2+释放（LCR）。LCR通过NCX产生内向电流，从而指数级加速晚期DD。LCR/INCX耦合事件的时间和幅度控制非线性终末DD的时间和幅度，因此最终通过确定引发下一个AP的L型钙电流（ICaL）激活时间来控制变时状态。LCR周期由SR Ca2+循环的动力学精确控制，而SR Ca2+循环的动力学又受以下因素调节：1）SR Ca2+循环蛋白依赖蛋白激酶A磷酸化的状态；2）确保Ca2+稳态以及因此确保Ca2+时钟可利用的Ca2+的膜离子通道。因此，早期研究中遗漏的早期DD与下一个AP之间的联系，由起搏细胞内精确生理调节的Ca2+时钟确保，该时钟整合多种Ca2+依赖性功能，并在晚期DD期间通过LCR-INCX耦合有节律地引发AP。
