The cover of Biophysical Journal (Volume 107, Issue 12) depicts a calcium “spark” occurring at a calcium release site in the cardiac myocyte. This is where calcium ions are released out of the sarcoplasmic reticulum through a cluster of release channels. The cell-wide calcium release comprises thousands of such spark events, which occur when the cell is electrically stimulated, thus leading to contraction. Sparks can also occur spontaneously and play an important role in myocyte physiology by contributing to calcium leak out of the sarcoplasmic reticulum. Furthermore, sparks can initiate cellular arrhythmias under pathological conditions. We used the model to show how changes to release channel regulation, membrane geometry, and release channel cluster structure, as observed in heart disease, alters calcium release and the occurrence of sparks.
Our model geometry was imported into the 3D rendering software Blender. We applied a translucent effect to the junctional sarcoplasmic reticulum to expose a packed cluster of green release channels. The structure of this cluster was determined using superresolution STED microscopy. The sparks, representing calcium ions, illuminate the scene; their positions and directions are determined by a simulation of a particle system subject to Brownian motion.
Our work is motivated by the desire to understand the molecular events leading to cardiac arrhythmias. Aberrant calcium release at these sites can lead to altered cell physiology and predispose the cell to arrhythmia-inducing afterdepolarizations. We used the model to predict the effects of cell structure remodeling, as observed in heart failure and catecholaminergic polymorphic ventricular tachycardia (CPVT). Improving our understanding of the calcium release process will help us advance therapies for these and other diseases.
Importantly, we have made this model available as a cloud-based service using the Galaxy research platform. Example simulation histories and workflows that produce the data featured in the article are available under Shared Data. Users may also customize the model, run simulations on cloud-based computing resources, and analyze the output through their web browser. The Galaxy server is available at: http://cvrg.galaxycloud.org/.
– Mark A. Walker, George S. B. Williams, Tobias Kohl, Stephan E. Lehnart, M. Saleet Jafri, Joseph L. Greenstein, W. J. Lederer, Raimond L. Winslow