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Cellular mechanisms of failure and arrhythmia in the diseased heart

N.A. Beard,1 A. Denniss,1 K. Walweel,2 D.R. Laver,2 P. Molenaar3,4 and A.F. Dulhunty,5 1Health Research Institute, Faculty of Education, Science, Technology and Mathematics, University of Canberra, Bruce, ACT, 2617, Australia, 2School of Biomedical Sciences and Pharmacy, University of Newcastle and Hunter Medical Research Institute, Callaghan, NSW 2308, Australia, 3Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, 4000, Australia, 4Northside Clinical School of Medicine, University of Queensland, The Prince Charles Hospital, Chermside, QLD, 4032, Australia and 5John Curtin School of Medical Research, Australian National University, Canberra, ACT 0200, Australia.

The RyR2 ligand-gated Ca2+ release channel is found embedded in the membrane of the intracellular Ca2+ store (the sarcoplasmic reticulum; SR), within the heart. It forms the hub of a large macromolecular complex that plays a vital role controlling cellular Ca2+ handling and specifically in SR Ca2+ release leading to systole. Maintaining a highly regulated and robust release of Ca2+ during systole and minimizing Ca2+ release, or leak, through the RyR2 during diastole is essential to healthy heart function. In heart failure, excess Ca2+ release or leak through RyR2 during diastole is prevalent. This leak is an arrhythmic substrate (Shannon et al., 2002), which can be induced by changes in channel sensitivity to Ca2+ (Marx et al., 2000; Terentyev et al., 2008; Walweel et al., 2017), the loss of regulatory co-factors and covalent modification by stress-induced reactive oxygen/nitrogen species and enhanced phosphokinase activity (reviewed in Dobrev et al., 2014).

We have previously shown that RyR2 is hyperphosphorylated at S2808 and S2814 and redox modified in human heart failure (Walweel et al., 2017). There is a reduction in the association of regulatory phosphatases with RyR2, which in part can account for the hyperphosphorylation observed in human heart failure patients (Walweel et al., 2017). These phosphor/redox-dependent changes correlate with a loss of channel responsiveness to Ca2+, and to a reduced association of the regulatory co-factors FKBP12 and FKBP12.6 from the channel (Walweel et al., 2017). Our results illustrate that changes in Ca2+ sensitivity are also observed in a number of other cardiac pathologies, including a model of RyR2-linked arrhythmogenic right ventricular cardiomyopathy and viral induced-myocarditis. Very recent data show a changed pattern of Ca2+ handling protein expression between atrial and ventricular healthy human heart tissue. Comparing failing heart atria and ventricle, we find not only very varied protein expression patterns, but also differences in phosphor/redox- RyR2 modification and RyR2 calcium handling.

Shannon TR, Ginsburg KS, Bers DM. (2002). Quantitative assessment of the SR Ca2+ leak-load relationship. Circ Res 91:594-600.

Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks AR. (2000). PKA phosphorylation dissociates FKBP12.6 from the calcium release channel: defective regulation in failing hearts. Cell 101:365-76.

Terentyev D, Gyorke I, Belevych AE, Terentyeva R, Sridhar A, Nishijima Y, de Dianco EC, Kanna S. Sen CK, Cardounel AJ, Carnes CA, Gyorke, S. (2008). Redox modification of ryanodine receptors contributes to sarcoplasmic reticulum Ca2+ leak in chronic heart failure. Circ Res 103:1466-72.

Walweel K, Molenaar P, Imtiaz MS, Denniss A, Dos Remedios C, van Helden DF, Dulhunty AF, Laver DR, Beard NA. (2017). Ryanodine receptor modification and regulation by intracellular Ca2+ and Mg2+ in healthy and failing human hearts. J Mol Cell Cardiol 104:53-62.