Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 98, Issue 20, Pages 11158-11162Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.201289098
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Funding
- NHLBI NIH HHS [HL52529, HL27430, R01 HL059130, HL04053, HL59130] Funding Source: Medline
- NIAMS NIH HHS [AR18687, R01 AR018687, R37 AR018687] Funding Source: Medline
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We have shown previously that at physiologically relevant oxygen tension (pO(2) approximate to 10 mmHg), NO S-nitrosylates 1 of approximate to 50 free cysteines per ryanodine receptor 1 (RyR1) subunit and transduces a calcium-sensitizing effect on the channel by means of calmodulin (CaM). It has been suggested that cysteine-3635 is part of a CaM-binding domain, and its reactivity is attenuated by CaM [Porter Moore, C., Zhang, J. Z., Hamilton, S. L. (1999) J. Biol. Chem. 274,36831-36834]. Therefore, we tested the hypothesis that the effect of NO was mediated by C3635. The full-length RyR1 single-site C3635A mutant was generated and expressed in HEK293 cells. The mutation resulted in the loss of CaM-dependent NO modulation of channel activity and reduced S-nitrosylation by NO to background levels but did not affect NO-independent channel modulation by CaM or the redox sensitivity of the channel to Oz and glutathione. Our results reveal that different cysteines within the channel have been adapted to serve in nitrosative and oxidative responses, and that S-nitrosylation of the cysteine-containing CaM-binding domain underlies the mechanism of CaM-dependent regulation of RyR1 by NO.
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