Subcellular calcium dynamics in a whole-cell model of an atrial myocyte

Thul, R�diger; Coombes, Stephen; Roderick, H. Llewelyn; Bootman, Martin D.

Abstract

In this study, we present an innovative mathematical modeling approach that allows detailed characterization of Ca 2+ movement within the three-dimensional volume of an atrial myocyte. Essential aspects of the model are the geometrically realistic representation of Ca 2+ release sites and physiological Ca 2+ flux parameters, coupled with a computationally inexpensive framework. By translating nonlinear Ca 2+ excitability into threshold dynamics, we avoid the computationally demanding time stepping of the partial differential equations that are often used to model Ca 2+ transport. Our approach successfully reproduces key features of atrial myocyte Ca 2+ signaling observed using confocal imaging. In particular, the model displays the centripetal Ca 2+ waves that occur within atrial myocytes during excitation-contraction coupling, and the effect of positive inotropic stimulation on the spatial profile of the Ca 2+ signals. Beyond this validation of the model, our simulation reveals unexpected observations about the spread of Ca 2+within an atrial myocyte. In particular, the model describes the movement of Ca 2+ between ryanodine receptor clusters within a specific z disk of an atrial myocyte. Furthermore, we demonstrate that altering the strength of Ca 2+ release, ryanodine receptor refractoriness, the magnitude of initiating stimulus, or the introduction of stochastic Ca 2+ channel activity can cause the nucleation of proarrhythmic traveling Ca 2+ waves. The model provides clinically relevant insights into the initiation and propagation of subcellular Ca 2+ signals that are currently beyond the scope of imaging technology.

Citation

Thul, R., Coombes, S., Roderick, H. L., & Bootman, M. D. (2012). Subcellular calcium dynamics in a whole-cell model of an atrial myocyte. Proceedings of the National Academy of Sciences, 109(6), 2150-2155. https://doi.org/10.1073/pnas.1115855109

• Journal Article Type: Article
• Publication Date: Feb 7, 2012
• Deposit Date: Dec 21, 2012
• Publicly Available Date: Dec 21, 2012
• Journal: Proceedings of the National Academy of Sciences
• Print ISSN: 0027-8424
• Electronic ISSN: 1091-6490
• Publisher: National Academy of Sciences
• Peer Reviewed: Peer Reviewed
• Volume: 109
• Issue: 6
• Pages: 2150-2155
• DOI: https://doi.org/10.1073/pnas.1115855109
• Public URL: https://nottingham-repository.worktribe.com/output/1009427
• Publisher URL: http://www.pnas.org/content/109/6/2150
• Additional Information: Copyright: National Academy of Sciences