Transmembrane redox sensor of ryanodine receptor complex

Inositol 1,4,5-trisphosphate receptors (IP3R) and ryanodine receptors (RyR) mediate the release of endoplasmic and sarcoplasmic reticulum (ER/SR) Ca2 stores and regulate Ca2+ entry through voltage-dependent or ligand-gated c hannels of the plasma membrane. A prominent property of ER/SR Ca2+ channels is exquisite sensitivity to sulfhydryl-modifying reagents. A plausible rol e for sulfhydryl chemistry in physiologic regulation of Ca2+ release channe ls and the fidelity of Ca2+ release from ER/SR is lacking. This study revea ls the existence of a transmembrane redox sensor within the RS RI channel c omplex that confers tight regulation of channel activity in response to cha nges in transmembrane redox potential produced by cytoplasmic and luminal g lutathione, A transporter selective for glutathione is co-localized with Ry R1 within the SR membrane to maintain local redox potential gradients consi stent with redox regulation of ER/SR Ca2+ release. Hyperreactive sulfhydryl s previously shown to reside within the RyR1 complex (Liu, G., and Pessah, I. N. (1994) J, Biol, Chem. 269, 33028-33034) are an essential biochemical component of a transmembrane redox sensor. Transmembrane redox sensing may represent a fundamental mechanism by which ER/SR Ca2+ channels respond to l ocalized changes in transmembrane glutathione redox potential produced by p hysiologic and pathophysiologic modulators of Ca2+ release from stores.