Nitric oxide protects the skeletal muscle Ca2+ release channel from oxidation induced activation.
Reactive oxygen intermediates and nitric oxide modulate the contractile function of skeletal muscle fibers, possibly via direct interaction with the Ca2+ release channel. Oxidants produce disulfide bonds between subunits of the Ca2+ release channel tetramer, and this is accompanied by an increase in channel activity. The sulfhydryl alkylating agent N-ethylmaleimide has three distinct effects on Ca2+ 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) (Aghdasi, B., Zhang, J. Z., Wu, Y., Reid, M. B., and Hamilton, S. L., (1997) J. Biol. Chem. 272, 3739-3749). Both H2O2 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 Ca2+ 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 Ca2+ release channel whereas higher concentrations oxidize it.
Aghdasi
B
B
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
Reid
M B
MB
Hamilton
S L
SL
D000478:Alkylation; D000818:Animals; D005033:Ethylmaleimide / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008051:Lipid Bilayers / Q000378:metabolism; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D010084:Oxidation-Reduction; D011487:Protein Conformation; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000378:metabolism
D008051:Lipid Bilayers; D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D005033:Ethylmaleimide