Vinogradova Tatiana M, Maltsev Victor A, Bogdanov Konstantin Y, Lyashkov Alexey E, Lakatta Edward G
Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Ann N Y Acad Sci. 2005 Jun;1047:138-56. doi: 10.1196/annals.1341.013.
Excitation-induced Ca(2+) cycling into and out of the cytosol via the sarcoplasmic reticulum (SR) Ca(2+) pump, ryanodine receptor (RyR) and Na(+)-Ca(2+) exchanger (NCX) proteins, and modulation of this Ca(2+)cycling by beta-adrenergic receptor (beta-AR) stimulation, governs the strength of ventricular myocyte contraction and the cardiac contractile reserve. Recent evidence indicates that heart rate modulation and chronotropic reserve via beta-ARs also involve intracellular Ca(2+) cycling by these very same molecules. Specifically, sinoatrial nodal pacemaker cells (SANC), even in the absence of surface membrane depolarization, generate localized rhythmic, submembrane Ca(2+) oscillations via SR Ca(2+) pumping-RyR Ca(2+) release. During spontaneous SANC beating, these rhythmic, spontaneous Ca(2+) oscillations are interrupted by the occurrence of an action potential (AP), which activates L-type Ca(2+) channels to trigger SR Ca(2+) release, unloading the SR Ca(2+) content and inactivating RyRs. During the later part of the subsequent diastolic depolarization (DD), when Ca(2+) pumped back into the SR sufficiently replenishes the SR Ca(2+) content, and Ca(2+)-dependent RyR inactivation wanes, the spontaneous release of Ca(2+) via RyRs again begins to occur. The local increase in submembrane [Ca(2+)] generates an inward current via NCX, enhancing the DD slope, modulating the occurrence of the next AP, and thus the beating rate. Beta-AR stimulation increases the submembrane Ca(2+) oscillation amplitude and reduces the period (the time from the prior AP triggered SR Ca(2+) release to the onset of the local Ca(2+) release during the subsequent DD). This increased amplitude and phase shift causes the NCX current to occur at earlier times following a prior beat, promoting the earlier arrival of the next beat and thus an increase in the spontaneous firing rate. Ca(2+) cycling via the SR Ca(2+) pump, RyR and NCX, and its modulation by beta-AR stimulation is, therefore, a general mechanism of cardiac chronotropy and inotropy.
通过肌浆网（SR）钙泵、兰尼碱受体（RyR）和钠钙交换体（NCX）蛋白，兴奋诱导钙离子进出细胞质，而β-肾上腺素能受体（β-AR）刺激对这种钙循环的调节，决定了心室肌细胞收缩的强度和心脏收缩储备。最近的证据表明，通过β-AR进行的心率调节和变时性储备也涉及这些相同分子介导的细胞内钙循环。具体而言，即使在没有表面膜去极化的情况下，窦房结起搏细胞（SANC）也会通过SR钙泵- RyR钙释放产生局部有节奏的、膜下钙离子振荡。在SANC自发搏动期间，这些有节奏的自发钙离子振荡会被动作电位（AP）的出现打断，动作电位激活L型钙通道以触发SR钙释放，耗尽SR钙含量并使RyR失活。在随后舒张期去极化（DD）的后期，当钙离子被泵回SR足以补充SR钙含量，且钙依赖性RyR失活减弱时，通过RyR的钙离子自发释放再次开始发生。膜下[Ca²⁺]的局部增加通过NCX产生内向电流，增强DD斜率，调节下一个AP的发生，从而调节搏动频率。β-AR刺激增加膜下钙离子振荡幅度并缩短周期（从前一个AP触发SR钙释放到随后DD期间局部钙释放开始的时间）。这种增加的幅度和相移导致NCX电流在前一次搏动后更早发生，促进下一次搏动更早到来，从而提高自发放电频率。因此，通过SR钙泵、RyR和NCX的钙循环及其受β-AR刺激的调节是心脏变时性和变力性的一般机制。
