Activation of the Cardiac Calcium Release Channel (Ryanodine Receptor) by Poly-S-Nitrosylation

TLDR

Redox‑responsive ion channels exist, yet the mechanisms underlying their activity changes remain unclear. The study investigated how nitric oxide modulates the canine cardiac ryanodine receptor. The CRC is a tetramer containing roughly 84 free thiols that undergo in vivo S‑nitrosylation. Poly‑S‑nitrosylation of up to 12 cysteines progressively activates the CRC in a reversible manner, whereas extensive oxidation has no effect or causes irreversible activation, showing that the channel distinguishes nitrosative from oxidative signals and is regulated by post‑translational sulfur modifications.

Abstract

Several ion channels are reportedly redox responsive, but the molecular basis for the changes in activity is not known. The mechanism of nitric oxide action on the cardiac calcium release channel (ryanodine receptor) (CRC) in canines was explored. This tetrameric channel contains ∼84 free thiols and is S-nitrosylated in vivo. S-Nitrosylation of up to 12 sites (3 per CRC subunit) led to progressive channel activation that was reversed by denitrosylation. In contrast, oxidation of 20 to 24 thiols per CRC (5 or 6 per subunit) had no effect on channel function. Oxidation of additional thiols (or of another class of thiols) produced irreversible activation. The CRC thus appears to be regulated by poly-S-nitrosylation (multiple covalent attachments), whereas oxidation can lead to loss of control. These results reveal that ion channels can differentiate nitrosative from oxidative signals and indicate that the CRC is regulated by posttranslational chemical modification(s) of sulfurs.