Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA031

Poster Communications

Subcellular organization of ryanodine receptors and Ca2+ channels modulates the propensity of spontaneous Ca2+ waves and cardiac arrhythmias

H. Sutanto1, B. V. Sloun1, P. Schönleitner2, M. V. Zanvoort3, G. Antoons2, J. Heijman1

1. Department of Cardiology, Maastricht University, Maastricht, Limburg, Netherlands. 2. Department of Physiology, Maastricht University, Maastricht, Limburg, Netherlands. 3. Department of Genetics & Cell Biology, Maastricht University, Maastricht, Limburg, Netherlands.

Ca2+ handling is a major factor influencing cardiac electrophysiology and its dysregulation plays a crucial role in cardiac arrhythmias. Spontaneous Ca2+-release events (SCaEs) from the sarcoplasmic reticulum play crucial roles in the initiation of cardiac arrhythmias by promoting triggered activity. However, the subcellular determinants of these SCaEs remain incompletely understood. Structural differences between atrial and ventricular cardiomyocytes, e.g., regarding the density of T-tubular membrane invaginations, may influence cardiomyocyte Ca2+-handling and the distribution of cardiac ryanodine receptors (RyR2) has recently been shown to undergo remodeling in atrial fibrillation. Recent publications (Brandenburg et al., 2016; Macquaide et al., 2015) have suggested that the subcellular distribution of RyR2, L-type Ca2+ channels (LTCC) and T-tubules in cardiomyocytes modulates Ca2+ handling, but it is experimentally challenging to directly study the impact of Ca2+-handling protein distributions (which require fixation and antibody staining) and Ca2+ handling in the same cell. Here, we employ computational modeling to provide an in-depth analysis of the impact of variations in subcellular RyR2 and LTCC distributions on Ca2+-transient properties and SCaEs in a human atrial cardiomyocyte model. We incorporate experimentally observed RyR2 expression patterns and various configurations of axial tubules, including previously published experimental axial tubules (Brandenburg et al., 2016) in a previously published model of the human atrial cardiomyocyte (Heijman, Erfanian Abdoust, Voigt, Nattel, & Dobrev, 2016; Voigt et al., 2014). We identify an increased SCaE incidence for larger heterogeneity in RyR2 expression (Fig. A, top), in which SCaEs preferentially arise from regions of high local RyR2 expression (Fig. A, bottom). We show that incorporation of axial tubules in various amounts and locations reduces Ca2+-transient time to peak (Fig. B). Although the LTCC distribution itself does not affect SCaEs, selective hyperphosphorylation of RyR2 around axial tubules increases the number of spontaneous waves. Finally, we present a novel model of the human atrial cardiomyocyte with physiological RyR2 and LTCC distributions that reproduces experimentally observed Ca2+-handling properties (Fig. C). Taken together, these results significantly enhance our understanding of the structure-function relationship in cardiomyocytes, identifying that RyR2 and LTCC distributions have a major impact on systolic Ca2+-transients and SCaEs.

Where applicable, experiments conform with Society ethical requirements