Transmembrane redox sensor of ryanodine receptor complex.
Inositol 1,4,5-trisphosphate receptors (IP(3)R) and ryanodine receptors (RyR) mediate the release of endoplasmic and sarcoplasmic reticulum (ER/SR) Ca(2+) stores and regulate Ca(2+) entry through voltage-dependent or ligand-gated channels of the plasma membrane. A prominent property of ER/SR Ca(2+) channels is exquisite sensitivity to sulfhydryl-modifying reagents. A plausible role for sulfhydryl chemistry in physiologic regulation of Ca(2+) release channels and the fidelity of Ca(2+) 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 Ca(2+) 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 Ca(2+) channels respond to localized changes in transmembrane glutathione redox potential produced by physiologic and pathophysiologic modulators of Ca(2+) release from stores.
Feng
W
W
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616, USA.
Liu
G
G
Allen
P D
PD
Pessah
I N
IN
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D003374:Coumarins / Q000378:metabolism; D005439:Flufenamic Acid; D005456:Fluorescent Dyes; D005470:Fluorometry; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D015640:Ion Channel Gating; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008564:Membrane Potentials; D010084:Oxidation-Reduction; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism
D002352:Carrier Proteins; D003374:Coumarins; D005456:Fluorescent Dyes; D008051:Lipid Bilayers; D019837:Ryanodine Receptor Calcium Release Channel; D013438:Sulfhydryl Compounds; D005439:Flufenamic Acid; C030860:N-(4-(7-diethylamino-4-methylcoumarin-3-yl)phenyl)maleimide; D005978:Glutathione; D002118:Calcium; D019803:Glutathione Disulfide