The Skeletal Muscle Calcium Release Channel

We report that pO2 dynamically controls the redox state of 6–8 out of 50 thiols in each RyR1 subunit and thereby tunes the response to NO

Jerry P Eu; Junhui Sun; Le Xu; Jonathan S Stamler; Gerhard Meissner

2004

Scholarcy highlights

  • Redox-related modifications of protein cysteine residues have emerged as molecular mechanisms behind many cellular processes, including DNA transcription, protein folding, chaperone activity, and enzyme function
  • It has been shown that O2 tension can modulate ion channel activities and that NO may play a role in O2 chemoreception, but again, the molecular details are not known
  • sarcoplasmic reticulum vesicles were probed with an excess of mBB, solubilized with detergent, and fractionated by sucrose density gradient centrifugation to isolate RyR1; the fluorescence intensity of each fraction was determined
  • During the experiment, matched SR preparations were probed withryanodine to identify the fraction most enriched with RyR1
  • S-nitrosothiol stoichiometry corresponded to ‫ف‬1 cysteine per RyR1 subunit, consistent with our previous data. Taken together with previous data, these results strongly suggest that at physiological NO and O2 concentrations, S-nitrosylation of one RyR1 cysteine per RyR1 subunit is a specific signaling event and not a result of random nitrosative modification
  • Our work provides a model for future studies of ion channels and other membrane proteins in which critical cysteines subserve coupled O2 sensor and NO regulatory functions
  • The demonstration that channel cysteine residues subserve coupled O2 sensor and NO regulatory functions and that these operate through the prototypic allosteric effector calmodulin may have general implications for the regulation of redox-related systems

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