期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 278, 期 10, 页码 8184-8189出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M211940200
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资金
- NHLBI NIH HHS [HL52529, HL59130, HL27430] Funding Source: Medline
- NIAMS NIH HHS [AR18687] Funding Source: Medline
The skeletal muscle Ca2+ release channel/ryanodine receptor (RyR1) contains similar to50 thiols per subunit. These thiols have been grouped according to their reactivity/responsiveness toward NO, O-2, and glutathione, but the molecular mechanism enabling redox active molecules to modulate channel activity is poorly understood. In the case of NO, very low concentrations (submicromolar) activate RyR1 by S-nitrosylation of a single cysteine residue (Cys-3635), which resides within a calmodulin binding domain. S-Nitrosylation of Cys-3635 only takes place at physiological tissue O-2 tension (pO(2); i.e. similar to10 mm Hg) but not at pO(2) similar to150 mm Hg. Two explanations have been offered for the loss of RyR1 responsiveness to NO at ambient pO(2), i.e. Cys-3635 is oxidized by O-2 versus O-2 subserves an allosteric function (Eu, J. P., Sun, J. H., Xu, L., Stamler, J. S., and Meissner, G. (2000) Cell 102, 499509). Here we report that the NO donors NOC-12 and S-nitrosoglutathione both activate RyR1 by release of NO but do so independently of pO(2). Moreover, NOC-12 activates the channel by S-nitrosylation of Cys-3635 and thereby reverses channel inhibition by calmodulin. In contrast, S-nitrosoglutathione activates RyRI by oxidation and S-nitrosylation of thiols other than Cys-3635 (and calmodulin is not involved). Our results suggest that the effect of pO(2) on RyR1 S-nitrosylation is exerted through an allosteric mechanism.
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