Regulation of the RyR channel gating by Ca and Mg.

Ryanodine receptors (RyRs) are the Ca release channels in the sarcoplasmic reticulum in striated muscle which play an important role in excitation-contraction coupling and cardiac pacemaking. Single channel recordings have revealed a wealth of information about ligand regulation of RyRs from mammalian skeletal and cardiac muscle (RyR1 and RyR2, respectively). RyR subunit has a Ca activation site located in the luminal and cytoplasmic domains of the RyR. These sites synergistically feed into a common gating mechanism for channel activation by luminal and cytoplasmic Ca. RyRs also possess two inhibitory sites in their cytoplasmic domains with Ca affinities of the order of 1 μM and 1 mM. Magnesium competes with Ca at these sites to inhibit RyRs and this plays an important role in modulating their Ca-dependent activity in muscle. This review focuses on how these sites lead to RyR modulation by Ca and Mg and how these mechanisms control Ca release in excitation-contraction coupling and cardiac pacemaking.