Luminal Ca(2+) activation of cardiac ryanodine receptors by luminal and cytoplasmic domains.

The ryanodine receptors form the calcium release channel in the membrane of the sarcoplasmic reticulum (SR, the main intracellular Ca(2+) store). The importance of ryanodine receptors (RyRs) to cardiac pacemaking and rhythmicity is highlighted by more than 69 mutations, RyR mutations, which underlie arrhythmias and sudden cardiac death. Although most of these mutations lie in cytoplasmic domains, they all cause increased RyR activation by Ca(2+) in the SR lumen. Presented here is a review of the mechanisms by which cytoplasmic domains of the RyR can determine luminal activation.