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Regulation of the RyR channel gating by Ca2+ and Mg2+

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Abstract

Ryanodine receptors (RyRs) are the Ca2+ 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 Ca2+ 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 Ca2+. RyRs also possess two inhibitory sites in their cytoplasmic domains with Ca2+ affinities of the order of 1 μM and 1 mM. Magnesium competes with Ca2+ at these sites to inhibit RyRs and this plays an important role in modulating their Ca2+-dependent activity in muscle. This review focuses on how these sites lead to RyR modulation by Ca2+ and Mg2+ and how these mechanisms control Ca2+ release in excitation-contraction coupling and cardiac pacemaking.

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Acknowledgments

Thanks to Dirk van Helden for suggesting the ‘Tipping Urn’ analogy in Fig. 2 and to Oliver Clarke for locating amino acids on the RyR1 structure in Fig. 1.

Funding

This work was supported by an infrastructure grant from NSW Health through Hunter Medical Research Institute.

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

    Derek R. Laver

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  1. Derek R. Laver
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Correspondence to Derek R. Laver.

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Derek R. Laver declares that he has no conflict of interest.

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This article does not contain any studies with human participants or animals performed by the author.

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This article is part of a Special Issue on ‘Heart Failure Due to Non-Myofibrillar Defects’ edited by Elisabeth Ehler and Katja Gehmlich.

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Laver, D.R. Regulation of the RyR channel gating by Ca2+ and Mg2+. Biophys Rev 10, 1087–1095 (2018). https://doi.org/10.1007/s12551-018-0433-4

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