Ca2+ in the Cleft
Fast and Fluorescent
Calcium ion (Ca2+) is a universal second messenger that governs a vast array of biological phenomena, including muscle contraction, neuronal transmission, fertilization, aging, cell death, and hormone secretion.1 Perturbations of intracellular Ca2+ signaling underlie a host of pathological states, including the myocardial diseases of ischemia/reperfusion injury, arrhythmia, myocyte hypertrophy, and heart failure.2
Article, see p 339
Despite the pivotal role of Ca2+ homeostasis in myocyte physiology and disease, large gaps exist in our understanding of its compartmentalization within subcellular microdomains and its trafficking among them. A vast literature has glossed over the finely tuned handling of intracellular Ca2+, its sites of storage, release, action, and reuptake, focusing instead on crude measures of bulk Ca2+ concentration. In so doing, the intricacies of spatiotemporal handling of Ca2+, occurring on the scales of milliseconds and nanometers, are blurred, and our understanding is incomplete.
Appreciation of the pivotal role of Ca2+ in heart function dates to the late 19th century, when Sidney Ringer3 discovered that this cation is absolutely required for cardiac mechanical function. Cardiac contraction is triggered by influx of a small amount of Ca2+ through voltage-gated l-type Ca2+ channels (LTCC) embedded in the cell surface membrane. This Ca2+ influx, in turn, triggers the release of much larger amounts of Ca2+ from sarcoplasmic reticulum (SR) stores through ryanodine receptors (RyRs), a process termed Ca2+-induced Ca2+ release. Thus, LTCC Ca2+ influx gates Ca2+-induced Ca2+ release; in the converse sense, Ca2+ released by Ca2+-induced Ca2+ release feeds back to control LTCC influx.4 The end result is an elaborate, finely tuned, and self-regulated cascade of events that controls every heart beat.
The intricate dynamics of this process …