Regulation of the RyR channel gating by Ca2+ and Mg2+
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.
KeywordsRyanodine receptor RyR1 RyR2 Excitation-contraction coupling Cardiac pacemaking Ca2+ activation Mg2+ inhibition Ca2+ release channels
This work was supported by an infrastructure grant from NSW Health through Hunter Medical Research Institute.
Compliance with ethical standards
Conflict of interest
Derek R. Laver declares that he has no conflict of interest.
This article does not contain any studies with human participants or animals performed by the author.
- Benkusky NA et al (2007) Intact beta-adrenergic response and unmodified progression toward heart failure in mice with genetic ablation of a major protein kinase A phosphorylation site in the cardiac ryanodine receptor. Circ Res 101:819–829. https://doi.org/10.1161/CIRCRESAHA.107.153007 CrossRefPubMedGoogle Scholar
- Bers DM (2002b) Cardiac excitation-contraction coupling. Nature 415Google Scholar
- Blazev R, Lamb GD (1999b) Low [ATP] and elevated [Mg2+] reduce depolarization-induced Ca2+ release in rat skinned skeletal muscle fibres. JPhysiolLond 520:203–215Google Scholar
- Cannell MB, Kong CH, Imtiaz MS, Laver DR (2013) Control of sarcoplasmic reticulum Ca2+ release by stochastic RyR gating within a 3D model of the cardiac dyad and importance of induction decay for CICR termination. Biophys J 104:2149–2159. https://doi.org/10.1016/j.bpj.2013.03.058 CrossRefPubMedPubMedCentralGoogle Scholar
- Fabiato A (1985) Simulated calcium current can both cause calcium loading in and trigger calcium release from the sarcoplasmic reticulum of a skinned canine cardiac Purkinje cell. JGenPhysiol 85:291–320Google Scholar
- Ferrero P, Said M, Sanchez G, Vittone L, Valverde C, Donoso P, Mattiazzi A, Mundina-Weilenmann C (2007) Ca2+/calmodulin kinase II increases ryanodine binding and Ca2+-induced sarcoplasmic reticulum Ca2+ release kinetics during beta-adrenergic stimulation. J Mol Cell Cardiol 43:281–291CrossRefPubMedPubMedCentralGoogle Scholar
- Fryer MW, Stephenson DG (1996) Total and sarcoplasmic reticulum calcium contents of skinned fibres from rat skeletal muscle. JPhysiolLond 493:357–370Google Scholar
- Godt RE, Maughan DW (1988) On the composition of the cytosol of relaxed skeletal muscle of the frog. AmJPhysiol 254:C591–C604Google Scholar
- Ju YK, Allen DG (1998) Intracellular calcium and Na+-Ca2+ exchange current in isolated toad pacemaker cells. JPhysiolLond 508:153–166Google Scholar
- Kurebayashi N, Ogawa Y (2001) Depletion of Ca2+ in the sarcoplasmic reticulum stimulates Ca2+ entry into mouse skeletal muscle fibres. JPhysiolLond 533:185–199Google Scholar
- Lamb GD, Stephenson DG (1994) Effects of intracellular pH and [Mg2+] on excitation-contraction coupling in skeletal muscle fibres of the rat. JPhysiolLond 478:331–339Google Scholar
- Laver D (2010) Regulation of the RyR channel gating by Ca, Mg and ATP. In structure-function of calcium release channels. In: Serysheva I (ed) Current topics in membranes, vol 66. Elsevier, pp 69–89Google Scholar
- Laver DR, Honen BN (2008) Luminal Mg2+, a key factor controlling RYR2-mediated Ca2+ release: cytoplasmic and luminal regulation modeled in a tetrameric channel. JGenPhysiol 132:429–446Google Scholar
- Laver DR, Lenz GK, Lamb GD (2001) Regulation of the calcium release channel from rabbit skeletal muscle by the nucleotides ATP, AMP, IMP and adenosine. JPhysiolLond 537:763–778Google Scholar
- Laver DR, O’Neill ER, Lamb GD (2004) Luminal Ca2+-regulated Mg2+ inhibition of skeletal RyRs reconstituted as isolated channels or coupled clusters. JGenPhysiol 124:741–758Google Scholar
- Peng W et al (2016) Structural basis for the gating mechanism of the type 2 ryanodine receptor RyR2. Science 354. https://doi.org/10.1126/science.aah5324
- Posterino GS, Lamb GD (2003) Effect of sarcoplasmic reticulum Ca2+ content on action potential-induced Ca2+ release in rat skeletal muscle fibres. JPhysiolLond 551:219–237Google Scholar
- Shomer NH, Louis CF, Fill M, Litterer LA, Mickelson JR (1993) Reconstitution of abnormalities in the malignant hyperthermia-susceptible pig ryanodine receptor. AmJPhysiol 264:C125–C135Google Scholar
- Smith JS, Coronado R, Meissner G (1986) Single channel measurements of the calcium release channel from skeletal muscle sarcoplasmic reticulum. Activation by Ca2+ and ATP and modulation by Mg2+. JGenPhysiol 88:573–588Google Scholar
- Zima AV, Picht E, Bers DM, Blatter LA (2008) Termination of cardiac Ca2+ sparks: role of intra-SR [Ca2+], release flux, and intra-SR Ca2+ diffusion Circ Res 103:e105–e115 doi:CIRCRESAHA.107.183236Google Scholar