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

Ryanodine-sensitive intracellular Ca(2+) channels (RyRs) open upon binding Ca(2+) at cytosolic-facing sites. This results in concerted, self-reinforcing opening of RyRs clustered in specialized regions on the membranes of Ca(2+) storage organelles (endoplasmic reticulum and sarcoplasmic reticulum), a process that produces Ca(2+)-induced Ca(2+) release (CICR). The process is optimized to achieve large but brief and localized increases in cytosolic Ca(2+) 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(2+) increase that results in contraction, as opposed to the flux activated directly by membrane depolarization (depolarization-induced Ca(2+) 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.