Calcium-induced release of calcium in muscle: 50 years of work and the emerging consensus.

Ryanodine-sensitive intracellular Ca channels (RyRs) open upon binding Ca at cytosolic-facing sites. This results in concerted, self-reinforcing opening of RyRs clustered in specialized regions on the membranes of Ca storage organelles (endoplasmic reticulum and sarcoplasmic reticulum), a process that produces Ca-induced Ca release (CICR). The process is optimized to achieve large but brief and localized increases in cytosolic Ca 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 Ca increase that results in contraction, as opposed to the flux activated directly by membrane depolarization (depolarization-induced Ca 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.