Calcium homeostasis in a local/global whole cell model of permeabilizedventricular myocytes with a Langevin description of stochastic calciumrelease

摘要

Population density approaches to modeling local control of Ca2+-induced Ca2+ release in cardiac myocytes can be used to constructminimal whole cell models that accurately represent heterogeneouslocal Ca2+ signals. Unfortunately, the computational complexity ofsuch “local/global” whole cell models scales with the number of Ca2+release unit (CaRU) states, which is a rapidly increasing function ofthe number of ryanodine receptors (RyRs) per CaRU. Here we presentan alternative approach based on a Langevin description of thecollective gating of RyRs coupled by local Ca2+ concentration([Ca2+]). The computational efficiency of this approach no longerdepends on the number of RyRs per CaRU. When the RyR model isminimal, Langevin equations may be replaced by a single Fokker-Planck equation, yielding an extremely compact and efficient local/global whole cell model that reproduces and helps interpret recentexperiments that investigate Ca2+ homeostasis in permeabilized ven-tricular myocytes. Our calculations show that elevated myoplasmic[Ca2+] promotes elevated network sarcoplasmic reticulum (SR)[Ca2+] via SR Ca2+-ATPase-mediated Ca2+ uptake. However, ele-vated myoplasmic [Ca2+] may also activate RyRs and promotestochastic SR Ca2+ release, which can in turn decrease SR [Ca2+].Increasing myoplasmic [Ca2+] results in an exponential increase inspark-mediated release and a linear increase in nonspark-mediatedrelease, consistent with recent experiments. The model exhibits twosteady-state release fluxes for the same network SR [Ca2+] dependingon whether myoplasmic [Ca2+] is low or high. In the later case,spontaneous release decreases SR [Ca2+] in a manner that maintainsrobust Ca2+ sparks.