Luminal Ca2+ controls termination and refractory behavior of Ca2+-induced Ca2+ release in cardiac myocytes
Luminal Ca2+ controls termination and refractory behavior of Ca2+-induced Ca2+ release in cardiac myocytes
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DOI：
10.1161/01.res.0000032490.04207.bd
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发表时间：
2002-09-06
影响因子：
20.1
通讯作者：
Györke, S
中科院分区：
文献类型：
--
作者：
Terentyev, D;Viatchenko-Karpinski, S;Györke, S
尽管有广泛的研究，但对心肌肌浆网（SR）中Ca 2+诱导的Ca 2+释放（CICR）的分级性质和早期终止的机制仍知之甚少。建议的机制包括细胞质Ca 2+依赖性失活/适应和腔Ca 2+依赖性失活SR Ca 2+释放通道/ryanodine受体（RyRs）。为了探索胞浆与腔Ca 2+调节机制在控制CICR中的重要性，我们评估了SR内Ca 2+缓冲对膜片钳或透化大鼠心室肌细胞的全局和局部Ca 2+释放特性的影响。通过将细胞暴露于含有缓冲液的“内部”溶液，将外源性低亲和力Ca 2+缓冲液（5至20 mmol/L ADA、柠檬酸盐或马来酸盐）引入SR中。增强的钙缓冲在SR中证实了总SR钙含量的增加，所揭示的咖啡因的应用。在全细胞水平，内SR [Ca 2 +]缓冲显着增加的幅度Ca 2+瞬变诱导的I-Ca和紊乱的平滑分级I-Ca-SR Ca 2+释放关系。局部Ca 2+释放事件、Ca 2+火花的幅度和到达峰值的时间以及火花下局部Ca 2+释放通量的持续时间增加了2至3倍。SR中的外源性Ca 2+缓冲液也降低了在RyR激活剂Imperatoxin A存在下在单个释放位点观察到的重复活性的频率。我们的结论是，RyR开放的调节局部内SR [Ca 2 +]是负责终止CICR和随后的恢复行为的Ca 2+释放网站在心肌中。
Despite extensive research, the mechanisms responsible for the graded nature and early termination of Ca2+-induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR) in cardiac muscle remain poorly understood. Suggested mechanisms include cytosolic Ca2+-dependent inactivation/adaptation and luminal Ca2+-dependent deactivtion of the SR Ca2+ release channels/ryanodine receptors (RyRs). To explore the importance of cytosolic versus luminal Ca2+ regulatory mechanisms in controlling CICR, we assessed the impact of intra-SR Ca2+ buffering on global and local Ca2+ release properties of patch-clamped or permeabilized rat ventricular myocytes. Exogenous, low-affinity Ca2+ buffers (5 to 20 mmol/L ADA, citrate or maleate) were introduced into the SR by exposing the cells to "internal" solutions containing the buffers. Enhanced Ca2+ buffering in the SR was confirmed by an increase in the total SR Ca2+ content, as revealed by application of caffeine. At the whole-cell level, intra-SR [Ca2+] buffering dramatically increased the magnitude of Ca2+ transients induced by I-Ca and deranged the smoothly graded I-Ca-SR Ca2+ release relationship. The amplitude and time-to-peak of local Ca2+ release events, Ca2+ sparks, as well as the duration of local Ca2+ release fluxes underlying sparks were increased up to 2- to 3-fold. The exogenous Ca2+ buffers in the SR also reduced the frequency of repetitive activity observed at individual release sites in the presence of the RyR activator Imperatoxin A. We conclude that regulation of RyR openings by local intra-SR [Ca2+] is responsible for termination of CICR and for the subsequent restitution behavior of Ca2+ release sites in cardiac muscle.