Regulation of ryanodine receptors by reactive nitrogen species

The ryanodine receptors (RyRs) are large intracellular calcium release channels that play an important role in the control of the calcium levels in excitable and non-excitable cells. Many endogenous modulators such as Mg2+, ATP, or calmodulin can affect the channel activities of the three known mammalian RyR isoforms. RyRs also are known to be redox-responsive. However, the molecular basis and the physiological relevance of redox modulation of RyRs are unclear. Recent evidence suggests that nitric oxide (NO) and related molecules may be endogenous regulators of the skeletal and cardiac muscle RyRs. The two tissues express nitric oxide synthases (NOSs), and NO or NO-related species have been shown to affect Ca2+ release channel activities directly via covalent modifications of thiol groups. Both an oxidative and a nitrosative modification of RyRs have been described, leading to either a reversible or irreversible alteration of RyR ion channel activity. Additional mechanisms of regulation may include cyclic GMP-dependent signaling pathways and NO modification of RyR regulatory proteins such as the surface membrane L-type Ca2+ channel. Modification of RyRs by NO may influence a variety of physiological functions such as insulin release, vasomotor control, and muscle contraction.