Abstract
Ryanodine receptors (RyRs) are the Ca(2+) 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(2+) 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(2+). RyRs also possess two inhibitory sites in their cytoplasmic domains with Ca(2+) affinities of the order of 1 μM and 1 mM. Magnesium competes with Ca(2+) at these sites to inhibit RyRs and this plays an important role in modulating their Ca(2+)-dependent activity in muscle. This review focuses on how these sites lead to RyR modulation by Ca(2+) and Mg(2+) and how these mechanisms control Ca(2+) release in excitation-contraction coupling and cardiac pacemaking.