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J. Biol. Chem. 275 (46): 35902-35907

© 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

Transmembrane Redox Sensor of Ryanodine Receptor Complex*

Wei FengDagger , Guohua LiuDagger , Paul D. Allen§, and Isaac N. PessahDagger

From the Dagger  Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616 and the § Department of Anesthesia, Brigham and Women's Hospital, Boston, Massachusetts 02114

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 channels of the plasma membrane. A prominent property of ER/SR Ca2+ channels is exquisite sensitivity to sulfhydryl-modifying reagents. A plausible role for sulfhydryl chemistry in physiologic regulation of Ca2+ release channels and the fidelity of Ca2+ release from ER/SR is lacking. This study reveals the existence of a transmembrane redox sensor within the RyR1 channel complex that confers tight regulation of channel activity in response to changes in transmembrane redox potential produced by cytoplasmic and luminal glutathione. A transporter selective for glutathione is co-localized with RyR1 within the SR membrane to maintain local redox potential gradients consistent with redox regulation of ER/SR Ca2+ release. Hyperreactive sulfhydryls 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 localized changes in transmembrane glutathione redox potential produced by physiologic and pathophysiologic modulators of Ca2+ release from stores.

* This work was supported by National Institutes of Health Grants 5RO1 AR43140 and 4PO1 AR17605.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Molecular Biosciences, School of Veterinary Medicine, University of California, One Shield Ave., Davis, CA 95616. Tel.: 530-752-6696; Fax: 530-752-4698; E-mail: inpessah@ucdavis.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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