Department of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom.
Biophys J. 2013 May 21;104(10):2149-59. doi: 10.1016/j.bpj.2013.03.058.
The factors responsible for the regulation of regenerative calcium-induced calcium release (CICR) during Ca(2+) spark evolution remain unclear. Cardiac ryanodine receptor (RyR) gating in rats and sheep was recorded at physiological Ca(2+), Mg(2+), and ATP levels and incorporated into a 3D model of the cardiac dyad, which reproduced the time course of Ca(2+) sparks, Ca(2+) blinks, and Ca(2+) spark restitution. The termination of CICR by induction decay in the model principally arose from the steep Ca(2+) dependence of RyR closed time, with the measured sarcoplasmic reticulum (SR) lumen Ca(2+) dependence of RyR gating making almost no contribution. The start of CICR termination was strongly dependent on the extent of local depletion of junctional SR Ca(2+), as well as the time course of local Ca(2+) gradients within the junctional space. Reducing the dimensions of the dyad junction reduced Ca(2+) spark amplitude by reducing the strength of regenerative feedback within CICR. A refractory period for Ca(2+) spark initiation and subsequent Ca(2+) spark amplitude restitution arose from 1), the extent to which the regenerative phase of CICR can be supported by the partially depleted junctional SR, and 2), the availability of releasable Ca(2+) in the junctional SR. The physical organization of RyRs within the junctional space had minimal effects on Ca(2+) spark amplitude when more than nine RyRs were present. Spark amplitude had a nonlinear dependence on RyR single-channel Ca(2+) flux, and was approximately halved by reducing the flux from 0.6 to 0.2 pA. Although rat and sheep RyRs had quite different Ca(2+) sensitivities, Ca(2+) spark amplitude was hardly affected. This suggests that moderate changes in RyR gating by second-messenger systems will principally alter the spatiotemporal properties of SR release, with smaller effects on the amount released.
调节钙火花演化过程中再生钙诱导钙释放（CICR）的因素尚不清楚。在生理 Ca²⁺、Mg²⁺和 ATP 水平下记录大鼠和绵羊的心脏兰尼碱受体（RyR）门控，并将其纳入心脏二联体的 3D 模型中，该模型再现了 Ca²⁺火花、Ca²⁺闪烁和 Ca²⁺火花恢复的时程。模型中 CICR 的终止主要是由于 RyR 关闭时间的陡峭 Ca²⁺依赖性，而测量的肌浆网（SR）腔 Ca²⁺对 RyR 门控的依赖性几乎没有贡献。CICR 终止的开始强烈依赖于连接 SR Ca²⁺局部耗竭的程度，以及连接间隙内局部 Ca²⁺梯度的时程。通过降低 CICR 内再生反馈的强度，减少二联体连接的 SR 钙火花幅度来减少二联体连接的尺寸。Ca²⁺火花起始和随后的 Ca²⁺火花幅度恢复的不应期源于 1）CICR 的再生相可以得到多大程度上部分耗尽的连接 SR 的支持，以及 2）连接 SR 中可释放的 Ca²⁺的可用性。当存在超过 9 个 RyR 时，RyR 在连接间隙中的物理组织对 Ca²⁺火花幅度的影响最小。火花幅度与 RyR 单通道 Ca²⁺通量呈非线性关系，当通量从 0.6 减少到 0.2 pA 时，幅度大约减半。尽管大鼠和绵羊的 RyR 具有非常不同的 Ca²⁺敏感性，但 Ca²⁺火花幅度几乎没有受到影响。这表明第二信使系统对 RyR 门控的适度改变主要会改变 SR 释放的时空特性，而对释放量的影响较小。
