Non-Thiol Reagents Regulate Ryanodine Receptor Function by Redox Interactions That Modify Reactive Thiols

The Ca2+ release channel (CRC) from sarcoplasmic reticulum (SR) is rich in thiol groups, and their oxidation/reduction by thiol reagents activates/inhibits the CRC. Most channel regulators are not thiol reagents, and the mechanism of their action is illusive. Here the authors show that many channel activators act as electron acceptors, while many channel inhibitors act as electron donors in free radical reactions. The channel activator, caffeine, and the CRC inhibitor, tetracaine, are shown to interact competitively, which suggests that there exists a common site(s) on the CRC, that integrates the donor/acceptor effects of ligands. Moreover, channel activators shift the redox potential of reactive thiols on the ryanodine receptor (RyR) to more negative values and decrease the number of reactive thiols, while channel inhibitors shift the redox potential to more positive values and increase the number of reactive thiols. These observations suggest that the non-thiol channel modulators shift the thiol-disulfide balance within CRC by transiently exchanging electrons with the Ca2+ release protein.