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

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Abstract

Contraction in skeletal and cardiac muscle occurs when Ca2+ is released from the sarcoplasmic reticulum (SR) through ryanodine receptor (RyR) Ca2+ release channels. Several isoforms of the RyR exist throughout the animal kingdom, which are modulated by ATP, Ca2+ and Mg2+ in the cytoplasm and by Ca2+ 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 Mg2+ is a potent RyR antagonist that binds to two classes of cytoplasmic site, identified as low-affinity, non-specific inhibition sites and high-affinity Ca2+ activation sites (A-sites). Mg2+ inhibition at the A-sites is very sensitive to the cytoplasmic and luminal milieu. Cytoplasmic Ca2+, Mg2+ and monovalent cations compete for the A-sites. In isolated RyRs, luminal Ca2+ alters the Mg2+ affinity of the A-site by an allosteric mechanism mediated by luminal sites. However, in close-packed RyR arrays luminal Ca2+ can also compete with cytoplasmic ions for the A-site. Activation of RyRs by luminal Ca2+ has been attributed to either Ca2+ feedthrough to A-sites or to Ca2+ regulatory sites on the luminal side of the RyR. As yet there is no consensus on just how luminal Ca2+ alters RyR activation. Recent evidence indicates that both mechanisms operate and are likely to be important. Allosteric regulation of A-site Mg2+ affinity could trigger Ca2+ release, which is reinforced by Ca2+ feedthrough.

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Acknowledgements

Thanks to G.D. Lamb for reading and commenting on the manuscript. This work was supported by the National Health and Medical Research Council of Australia (grant number 234420) and by an infrastructure grant from NSW Health through Hunter Medical Research Institute. This work was supported by a Professorial Fellowship from the Australian Research Council.

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  1. School of Biomedical Sciences, University of Newcastle and Hunter Medical Research Institute, Callaghan, NSW, 2308, Australia

    Derek R. Laver

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Laver, D.R. Coupled calcium release channels and their regulation by luminal and cytosolic ions. Eur Biophys J 34, 359–368 (2005). https://doi.org/10.1007/s00249-005-0483-y

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