Coupled calcium release channels and their regulation by luminal and cytosolic ions

Contraction in skeletal and cardiac muscle occurs when Ca(2+) is released from the sarcoplasmic reticulum (SR) through ryanodine receptor (RyR) Ca(2+) release channels. Several isoforms of the RyR exist throughout the animal kingdom, which are modulated by ATP, Ca(2+) and Mg(2+) in the cytoplasm and by Ca(2+) in the lumen of the SR. This review brings to light recent findings on their mechanisms of action in the mammalian isoforms RyR-1 and RyR-2 with an emphasis on RyR-1 from skeletal muscle. Cytoplasmic Mg(2+) is a potent RyR antagonist that binds to two classes of cytoplasmic site, identified as low-affinity, non-specific inhibition sites and high-affinity Ca(2+) activation sites (A-sites). Mg(2+) inhibition at the A-sites is very sensitive to the cytoplasmic and luminal milieu. Cytoplasmic Ca(2+), Mg(2+) and monovalent cations compete for the A-sites. In isolated RyRs, luminal Ca(2+) alters the Mg(2+) affinity of the A-site by an allosteric mechanism mediated by luminal sites. However, in close-packed RyR arrays luminal Ca(2+) can also compete with cytoplasmic ions for the A-site. Activation of RyRs by luminal Ca(2+) has been attributed to either Ca(2+) feedthrough to A-sites or to Ca(2+) regulatory sites on the luminal side of the RyR. As yet there is no consensus on just how luminal Ca(2+) alters RyR activation. Recent evidence indicates that both mechanisms operate and are likely to be important. Allosteric regulation of A-site Mg(2+) affinity could trigger Ca(2+) release, which is reinforced by Ca(2+) feedthrough.