Modeling Calcium Sparks in a Three-Dimensional Reconstruction of a Cardiac Calcium Release Unit

Abstract

A Ca2+ spark is the fundamental unit of Ca2+ release from the sarcoplasmic reticulum (SR) during excitation-contraction coupling, and the major contributor to diastolic Ca2+ leak in cardiomyocytes. The duration and magnitude of the spark is determined by the local geometry of a single Ca2+ release unit (CRU) as well as the localization and density of Ca2+ handling proteins. We have developed a detailed computational model of a single CRU situated in its native structural cellular environment. The geometry was generated using newly developed computational tools from electron microscopic tomography data, and it includes sarcoplasmic reticulum (SR), t-tubules, and mitochondria. Ca2+ diffusion is modeled both within the SR lumen and in the cytosol. The model is used to examine the effect of localization and density of the Na+ /Ca2+ exchanger (NCX) and sarco-endoplasmic reticulum Ca2+ ATPase (SERCA) pump. Our findings are: 1) including NCX in the CRU exhausts Ca2+ from the CRU during a spark significantly, 2) high SERCA density close to the CRU prolongs spark duration by preventing luminal depletion of Ca2+ ions.