Macroscopic consequences of calcium signaling in microdomains: a first-passage-time approach.

Calcium (Ca) plays an important role in regulating various cellular processes. In a variety of cell types, Ca signaling occurs within microdomains where channels deliver localized pulses of Ca activating a nearby collection of Ca-sensitive receptors. The small number of channels involved ensures that the signaling process is stochastic. The aggregate response of several thousand of these microdomains yields a whole-cell response which dictates the cell behavior. Here, we study the statistical properties of a population of these microdomains in response to a trigger signal. We use a first-passage-time approach to show analytically how Ca release in the whole cell depends on properties of Ca channels within microdomains. Using these results we explain for the first time the underlying mechanism for the graded relationship between Ca influx and Ca release in cardiac cells.