Ca2+ signaling in mouse cardiomyocytes with ablated S100A1 protein
Ca2+ signaling in mouse cardiomyocytes with ablated S100A1 protein
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DOI：
10.4149/gpb_2009_04_371
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发表时间：
2009-12-01
影响因子：
1.5
通讯作者：
Niggli, Ernst
中科院分区：
文献类型：
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作者：
Gusev, Konstantin;Ackermann, Gabriele E.;Niggli, Ernst
S100 A1是心肌中高水平表达的Ca 2+结合蛋白。它被认为调节肌浆网（SR）Ca 2+释放通道（ryanodine受体或RyR）的Ca 2+敏感性，并且其表达已显示在各种心脏疾病中下调。在这项研究中，我们使用S100 A1基因敲除（KO）小鼠研究慢性S100 A1缺陷对心室肌细胞Ca 2+循环的影响。共聚焦钙离子成像显示，场刺激KO心肌细胞在对照条件下有接近正常的钙离子信号，但对β-肾上腺素能刺激1 μ mol/l异丙肾上腺素（ISO）的反应迟钝。电压钳实验表明，S100 A1缺陷的心肌细胞在基础条件下具有升高的I-Ca。这种较大的Ca 2+内流伴随着增强的Ca 2+瞬变和升高的SR Ca 2+含量，而没有宏观兴奋-收缩耦合增益的变化，这表明受损的部分Ca 2+释放。KO和WT细胞暴露于ISO导致相似的最大I-Ca。因此，在KO心肌细胞中，I-Ca的刺激不太明显，表明基础I-Ca的变化可能是P-肾上腺素能反应降低的基础。两者合计，我们的研究结果表明，长期缺乏S100 A1的结果在增强的L-型钙离子通道活性与钝化SR钙释放放大相结合。这些发现可能对各种心脏病理有影响，其中描述了异常RyR Ca 2+敏感性或S100 A1水平降低。
S100A1 is a Ca2+-binding protein expressed at high levels in the myocardium. It is thought to modulate the Ca2+ sensitivity of the sarcoplasmic reticulum (SR) Ca2+ release channels (ryanodine receptors or RyRs) and its expression has been shown to be down regulated in various heart diseases. In this study we used S100A1 knock-out (KO) mice to investigate the consequences of chronic S100A1 deficiency on Ca2+ cycling in ventricular cardiomyocytes. Confocal Ca2+ imaging showed that field-stimulated KO myocytes had near normal Ca2+ signaling under control conditions but a blunted response to beta-adrenergic stimulation with 1 mu mol/l isoproterenol (ISO). Voltage-clamp experiments revealed that S100A1-deficient cardiomyocytes have elevated I-Ca under basal conditions. This larger Ca2+ influx was accompanied by augmented Ca2+ transients and elevated SR Ca2+ content, without changes in macroscopic excitation-contraction coupling gain, which suggests impaired fractional Ca2+ release. Exposure of KO and WT cells to ISO led to similar maximal I-Ca. Thus, the stimulation of the I-Ca was less pronounced in KO cardiomyocytes, suggesting that changes in basal I-Ca could underlie the reduced P-adrenergic response. Taken together, our findings indicate that chronic absence of S100A1 results in enhanced L-type Ca2+ channel activity combined with a blunted SR Ca2+ release amplification. These findings may have implications in a variety of cardiac pathologies where abnormal RyR Ca2+ sensitivity or reduced S100A1 levels have been described.