Membrane repolarization stops caffeine-induced Ca2+ release in skeletal muscle cells.

We have combined the patch-clamp technique with fura-2 measurements to investigate whether the Ca(2+)-induced Ca(2+)-release channel is under the control of membrane potential in rat skeletal myoballs. We report that Ca2+ release induced by 10 mM caffeine is turned off by membrane repolarization, a phenomenon that we term RISC (repolarization-induced stop of Ca2+ release). The RISC phenomenon is voltage- and time-dependent. It is evident only when the release channels are first transferred into a functionally "voltage-activated" state through membrane depolarization. The results demonstrate that membrane repolarization actively closes the caffeine-activated release channels and suggest that the ryanodine receptor is actually the physiological depolarization-induced Ca(2+)-release channel. Thus, our data provide compelling evidence for a bidirectional voltage control (depolarization and repolarization) of the Ca(2+)-release channel in the sarcoplasmic reticulum by a voltage sensor in the transverse tubule membrane.