Nitric oxide protects the skeletal muscle Ca super(2+) release channel from oxidation induced activation

• Published in: The Journal of biological chemistry Vol. 272; no. 41; pp. 25462 - 25467
• Main Authors: Aghdasi, B, Reid, M B, Hamilton, S L
• Format: Journal Article
• Language: English
• Published: 01.10.1997
• ISSN: 0021-9258

Reactive oxygen intermediates and nitric oxide modulate the contractile function of skeletal muscle fibers, possibly via direct interaction with the Ca super(2+) release channel. Oxidants produce disulfide bonds between subunits of the Ca super(2+) release channel tetramer, and this is accompanied by an increase in channel activity. The sulfhydryl alkylating agent N-ethylmaleimide has three distinct effects on Ca super(2+) release channel activity: first, channel activity is decreased (phase 1); then with continued exposure the activity is dramatically increased (phase 2); and finally, the channel is again inhibited (phase 3). Both H sub(2)O sub(2) and nitric oxide (NO) block the phase 1 inhibitory effect of N-ethylmaleimide. NO donors, at concentrations that have no detectable effect on channel activity, block intersubunit cross-linking and prevent activation of the channel by the disulfide inducing agent, diamide. These findings support a model in which NO modulates the activity of the Ca super(2+) release channel by preventing oxidation of regulatory sulfhydryls. However, higher concentrations of NO donors activate the channel and produce intersubunit cross-links, supporting a bifunctional effect of NO on channel activity. Low NO concentrations prevent oxidation of the Ca super(2+) release channel whereas higher concentrations oxidize it.