Local calcium gradients during excitation-contraction coupling and alternans in atrial myocytes
Local calcium gradients during excitation-contraction coupling and alternans in atrial myocytes
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DOI：
10.1113/jphysiol.2002.025239
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发表时间：
2003-01-01
影响因子：
5.5
通讯作者：
Lipsius, SL
中科院分区：
文献类型：
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作者：
Blatter, LA;Kockskämper, J;Lipsius, SL
使用快速共聚焦显微镜和测量Ca2+电流（I-Ca）在心房肌细胞中研究了正常兴奋-收缩（E-C）偶联和Ca2+交替期间的亚细胞Ca2+信号。Ca2+交替，一种[Ca2+](i)瞬态振幅的搏动交替，导致机电交替，这与心脏颤动和心源性猝死的产生有关。猫心房肌细胞缺乏横小管，含有连接型（j-SR）和非连接型（nj-SR）的肌浆网（SR），两者都有红嘌呤受体钙释放通道。在E-C偶联过程中，Ca2+通过电压门控膜Ca2+通道（ICa）进入触发离散外周j-SR释放位点的Ca2+释放。离散的Ca2+火花样增加[Ca2+](i)，然后融合到升高的[Ca2+](i)的外周“环”中，随后繁殖（通过钙诱导的Ca2+释放，CICR）到细胞中心，导致收缩。中断I-Ca立即终止j-SR Ca2+释放，而nj-SR Ca2+释放继续。增加刺激频率或抑制糖酵解引起Ca2+交替。交替期间的时空[Ca2+](i)模式显示出明显的亚细胞异质性，包括[Ca2+](i)和邻近亚细胞区域的纵向和横向梯度。此外，糖酵解的局部抑制导致空间限制的Ca2+交替，进一步强调了这种现象的局部特征。当肌细胞内的两个相邻区域交替出相时，延迟传播的Ca2+波在其边界发展。综上所述，结果表明：(1)在正常E-C偶联期间，心房[Ca2+](i)瞬态是外周j-SR和中央nj-SR的单个释放位点Ca2+释放的时空总和的结果，CICR分别通过i - ca和j-SR的Ca2+释放以向心方式激活；(2)Ca2+交替是由SR Ca2+释放的亚细胞改变引起的，至少部分是由局部能量代谢抑制引起的。(3)由亚细胞Ca2+互变的异质性引起的致心律失常Ca2+波的产生可能构成心律失常发展的新机制。
Subcellular Ca2+ signalling during normal excitation-contraction (E-C) coupling and during Ca2+ alternans was studied in atrial myocytes using fast confocal microscopy and measurement of Ca2+ currents (I-Ca). Ca2+ alternans, a beat-to-beat alternation in the amplitude of the [Ca2+](i) transient, causes electromechanical alternans, which has been implicated in the generation of cardiac fibrillation and sudden cardiac death. Cat atrial myocytes lack transverse tubules and contain sarcoplasmic reticulum (SR) of the junctional (j-SR) and non-junctional (nj-SR) types, both of which have ryanodine-receptor calcium release channels. During E-C coupling, Ca2+ entering through voltage-gated membrane Ca2+ channels(ICa)triggers Ca2+ release at discrete peripheral j-SR release sites. The discrete Ca2+ spark-like increases of [Ca2+](i) then fuse into a peripheral 'ring' of elevated [Ca2+](i), followed by propagation (via calcium-induced Ca2+ release, CICR) to the cell centre, resulting in contraction. Interrupting I-Ca instantaneously terminates j-SR Ca2+ release, whereas nj-SR Ca2+ release continues. Increasing the stimulation frequency or inhibition of glycolysis elicits Ca2+ alternans. The spatiotemporal [Ca2+](i) pattern during alternans shows marked subcellular heterogeneities including longitudinal and transverse gradients of [Ca2+](i) and neighbouring subcellular regions alternating out of phase. Moreover, focal inhibition of glycolysis causes spatially restricted Ca2+ alternans, further emphasising the local character of this phenomenon. When two adjacent regions within a myocyte alternate out of phase, delayed propagating Ca2+ waves develop at their border. In conclusion, the results demonstrate that (1) during normal E-C coupling the atrial [Ca2+](i) transient is the result of the spatiotemporal summation of Ca2+ release from individual release sites of the peripheral j-SR and the central nj-SR, activated in a centripetal fashion by CICR via I-Ca and Ca2+ release from j-SR, respectively, (2) Ca2+ alternans is caused by subcellular alterations of SR Ca2+ release mediated, at least in part, by local inhibition of energy metabolism, and (3) the generation of arrhythmogenic Ca2+ Waves resulting from heterogeneities in subcellular Ca2+ alternans may constitute a novel mechanism for the development of cardiac dysrhythmias.