Abstract:
Ryanodine-sensitive intracellular Ca2+ channels (RyRs) open upon binding Ca2+ at cytosolic-facing sites. This results in concerted, self-reinforcing opening of RyRs clustered in specialized regions on the membranes of Ca2+ storage organelles (endoplasmic reticulum and sarcoplasmic reticulum), a process that produces Ca2+-induced Ca2+ release (CICR). The process is optimized to achieve large but brief and localized increases in cytosolic Ca2+ concentration, a feature now believed to be critical for encoding the multiplicity of signals conveyed by this ion. In this paper, I trace the path of research that led to a consensus on the physiological significance of CICR in skeletal muscle, beginning with its discovery. I focus on the approaches that were developed to quantify the contribution of CICR to the Ca2+ increase that results in contraction, as opposed to the flux activated directly by membrane depolarization (depolarization-induced Ca2+ release [DICR]). Although the emerging consensus is that CICR plays an important role alongside DICR in most taxa, its contribution in most mammalian muscles appears to be limited to embryogenesis. Finally, I survey the relevance of CICR, confirmed or plausible, to pathogenesis as well as the multiple questions about activation of release channels that remain unanswered after 50 years.
摘要:
Ryanodine敏感的细胞内Ca2通道(RyRs)在面向细胞溶质的位点结合Ca2后打开。这导致了一致,RyRs的自我增强开放聚集在Ca2储存细胞器(内质网和肌浆网)膜上的专门区域,产生Ca2+诱导的Ca2+释放(CICR)的过程。该过程进行了优化,以实现胞质Ca2+浓度的大而短暂和局部的增加,现在被认为是编码由这个离子传送的信号的多样性的关键特征。在本文中,我追踪了导致对骨骼肌中CICR的生理意义达成共识的研究路径,从发现开始。我专注于为量化CICR对导致收缩的Ca2增加的贡献而开发的方法,与膜去极化(去极化诱导的Ca2释放[DICR])直接激活的通量相反。尽管新兴的共识是CICR在大多数分类单元中与DICR一起发挥着重要作用,它在大多数哺乳动物肌肉中的作用似乎仅限于胚胎发生。最后,我调查了CICR的相关性,证实或似是而非,发病机理以及50年后仍未解决的释放通道激活的多个问题。