Molecular interaction between nitric oxide and ryanodine receptors of skeletal and cardiac sarcoplasmic reticulum.

In striated muscle, the sarcoplasmic reticulum (SR) is the major storage compartment of intracellular Ca2+ that controls cytosolic free Ca2+ (Cai) and developed force by sequestering and releasing Ca2+ during each contraction. Ca2+ release from the SR occurs through high-conductance Ca2+ release channels or ryanodine receptors (RyR), which are regulated by various signaling processes. Over the last 15 years, there has been a growing consensus that critical sulfhydryl sites on RyRs can be oxidized and reduced, respectively, to open and close the release channels. The pharmacological actions of various classes of sulfhydryl reagents have demonstrated the existence of hyperreactive thiols on RyRs, which could play a role in the regulation of normal contractile function and explain contractile dysfunctions in pathological conditions. More recent studies show that redox regulation of release channels may occur by nitric oxide (NO), a physiological signaling mechanism. This article is intended to review current concepts in thiol regulation of RyRs and present new data on the possible identification of the primary cysteine residues, which may be the site of oxidation and S-nitrosylation involved in channel opening.