Hyperreactive sulfhydryl groups associated with the Ca(2+) release protein from sarcoplasmic reticulum are shown to have a well defined reduction potential that is sensitive to the cellular environment. Ca(2+) channel activators lower the redox potential of the ryanodine receptor, which favors the oxidation of thiols and the opening of the Ca(2+) release protein. In contrast, channel inhibitors increase the redox potential, which favors the reduction of disulfides and the closure of the release protein. Modulation of redox potential of reactive thiols may be a general control mechanism by which sarcoplasmic/endoplasmic reticulum, ryanodine receptors/IP(3) receptors, control cytoplasmic Ca(2+) concentrations.