Calcium handling in embryonic stem cell-derived cardiac myocytes - Of mice and men
Calcium handling in embryonic stem cell-derived cardiac myocytes - Of mice and men
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DOI：
10.1196/annals.1380.017
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发表时间：
2006-01-01
期刊：
影响因子：
--
通讯作者：
Gepstein, Lior
中科院分区：
文献类型：
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作者：
Itzhaki, Ilanit;Schiller, Jackie;Gepstein, Lior
兴奋-收缩 (EC) 耦合是心肌细胞 (CM) 功能的基础。在成熟的肌细胞质膜 (PM) 中，L 型 Ca2+ 通道与肌浆网 (SR) 膜上的兰尼碱受体 (RyR) 紧密结合发挥作用。动作电位 (AP) 导致 PM L 型 Ca2+ 通道打开，进而为更大的 RyR 介导的 SR Ca2+ 释放提供触发 Ca2+。相反，发育中的肌细胞的 SR 发育较差。在小鼠胚胎干细胞来源的心肌细胞（ESC-CM）的早期和中期成熟阶段观察到这种不完全发育。尽管缺乏发育良好的 T 管系统，鼠 ESC-CM 使用内部 Ca2+ 储备进行 EC 耦合。 Ca2+ 处理的直接测量，包括药理学研究和转基因小鼠 ESC-CM 的研究，确定了 RyR 介导的内部 Ca2+ 储存对细胞功能的重要贡献。同样，早期人类 ESC-CM 使用内部 Ca2+ 存储，并与鼠 ESC-CM 部分共享 Ca2+ 处理特性。例如，基本 Ca2+ 释放事件存在于小鼠和人类 ESC-CM 中，并且 Ca2+ 处理可能有助于这些细胞中自动节律的产生。然而，在人类 ESC-CM 中，独特的电压门控 Na+ 通道窗口电流对于自发、节律性去极化至关重要。小鼠和人类 ES 心肌细胞分化系统的出现为哺乳动物心脏兴奋性和机电耦合发展的早期步骤提供了初步见解，包括基因表达模式、肌原纤维形成、离子通道发育和功能以及 Ca2+ 处理。在这里，我们讨论从这些模型中获得的信息，以描述电压门控通道电流和 Ca2+ 对节律活动的处理之间的关系。
Excitation-contraction (EC) coupling is fundamental to the function of cardiac myocytes (CMs). In mature myocytes plasma membrane (PM) L-type Ca2+ channels function in close juxtaposition to ryanodine receptors (RyR) on the sarcoplasmic reticulum (SR) membrane. Action potentials (APs) cause the opening of PM L-type Ca2+ channels, which in turn provide trigger Ca2+ for a larger RyR-mediated SR Ca2+ release. In contrast, developing myocytes have a less well-developed SR. This incomplete development is observed in early stage and midmaturation stages of murine embryonic stem cell-derived cardiac myocytes (ESC-CMs). Despite the absence of a well-developed t-tubule system, murine ESC-CMs use internal Ca2+ stores for EC coupling. Direct measures of Ca2+ handling, including pharmacological studies and investigation of genetically modified mouse ESC-CMs, established an important contribution of RyR-mediated internal Ca2+ store to cell function. Similarly, early-stage human ESC-CMs use internal Ca2+ store and partially share Ca2+ handling characteristics with murine ESC-CMs. For example, elementary Ca2+ release events are present in both murine and human ESC-CMs, and it is likely that Ca2+ handling contributes to automatic rhythm generation in these cells. However, in human ESC-CMs, a unique voltage-gated Na+ channel window current is critical for spontaneous, rhythmic depolarization. The advent of the murine and human ES cardiomyocyte differentiating systems has provided initial insights into the early steps of development of excitability and electromechanical coupling in the mammalian heart, including patterns of gene expression, myofibrillogenesis, ion channel development and function, and Ca2+ handling. Here we discuss the information gained from these models to describe the nexus of voltage-gated channel currents and Ca2+ handling on rhythmic activity.