Triggered release of Ca2+ from an individual calcium release unit (CRU), known as a Ca2+ spark, is the fundamental event of cardiac excitation–contraction coupling. Spontaneous Ca2+ sparks are the major contributor to diastolic Ca2+ leak in heart failure. Previous models have predicted that the duration and magnitude of the spark is determined by the local CRU geometry and the localization and density of Ca2+ handling proteins. To test these hypotheses, we have developed a detailed, particle-based computational model of a cardiac Ca2+ spark based on 3D reconstructions of CRU from electron tomography. Our model, created with MCell, a Monte Carlo Cell simulator, is able to track the position and reactions between thousands of Ca2+ molecules, Ca2+-handling proteins, and Ca2+ pumps. In our parameterization of the CRU model, we have also created a particle-based model of the Sarco/Endoplasmic Reticulum Calcium ATP-ase (SERCA) pump that is sensitive to changes in pH. This new model will provide a more comprehensive understanding of the dynamic chemistry occurring at the dyadic junction—the interface of the TT and SR—shedding light on the fundamentals of heart function and disease.

Stochastic model of Ca2+ sparks in cardiomyocytes: Using MCell to investigate the fundamental sub-cellular processes of the heartbeat

251st National Meeting (2016)

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