Calcium in close quarters: Microdomain feedback in excitation-contraction coupling and other cell biological phenomena

Researchers have made good progress in unraveling the molecular mechanisms of excitation-contraction (EC) coupling in striated muscle. Despite this progress, paradoxes abound. In skeletal muscle, the existence of a mechanical coupling between membrane charge movement and activation of sarcoplasmic reticulum (SR) release channels is essentially established, but the contribution of Ca2+-induced Ca2+ release (CICR) to the transient and steady-state components of Ca2+ release remains controversial. In cardiac muscle, the role of CICR as the primary mechanism of EC coupling is well established, but the stability and tight coupling between membrane Ca2+ current and release are paradoxical. Answers may lie in microdomain issues, and in the examination of discrete elementary release events, although quantitative treatments are needed. This review explores the theoretical and experimental methods used and the observations made in the study of microdomain Ca2+.