Impact of subcellular distribution of calcium-handling proteins in atrial cardiomyocytes

We have recently extended our previous spatial calcium-handling model of the human atrial cardiomyocyte (Voigt, Heijman et al. Circulation 2014) to simulate heterogeneous distributions of ryanodine receptor (RyR) channels and L-type calcium channels (in axial tubules). We employed the perfect control and observability provided by this computer model to overcome experimental challenges in the analysis of the subcellular determinants of cardiomyocyte calcium handling. Our work identifies an increased SCaE incidence for larger heterogeneity in RyR expression (Figure), in which SCaEs preferentially arise from regions of high local RyR expression. Importantly, whole-cell calcium-handling properties are determined by nonlinear interactions between heterogeneities in the properties (expression, phosphorylation) of both L-type calcium channels and RyR, highlighting the need for detailed immunocytochemistry and functional studies to explain differences in whole-cell calcium-handling properties between conditions.

The computer model employed in this study (a combination of C++ and Octave code) can be downloaded using the link below:

HAMM 2018 Model

Human atrial myocyte model with spatial calcium handling and RyR heterogeneity used in Sutanto et al. Front Physiol.

Reference: Sutanto Hvan Sloun B, Schönleitner P, van Zandvoort MAMJ, Antoons G, Heijman J (2018) The Subcellular Distribution of Ryanodine Receptors and L-type Ca2+ Channels Modulates Ca2+-transient Properties and Spontaneous Ca2+-release Events in Atrial Cardiomyocytes. Front Physiol, Manuscript accepted on July 23, 2018