Document Type
Article
Department/Program
Applied Science
Journal Title
American Journal of Physiology-Heart and Circulatory Physiology
Pub Date
3-2015
Volume
308
Issue
5
First Page
H510
Abstract
Population density approaches to modeling local control of Ca2+ induced Ca2+ release in cardiac myocytes can be used to construct minimal whole cell models that accurately represent heterogeneous local Ca2+ signals. Unfortunately, the computational complexity of such "local/global" whole cell models scales with the number of Ca2+ release unit (CaRU) states, which is a rapidly increasing function of the number of ryanodine receptors (RyRs) per CaRU. Here we present an alternative approach based on a Langevin description of the collective gating of RyRs coupled by local Ca2+ concentration ([Ca2+]). The computational efficiency of this approach no longer depends on the number of RyRs per CaRU. When the RyR model is minimal, 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 recent experiments that investigate Ca2+ homeostasis in permeabilized ventricular myocytes. Our calculations show that elevated myoplasmic [Ca2+] promotes elevated network sarcoplasmic reticulum (SR) [Ca2+] via SR Ca2+ -ATPase-mediated Ca2+ uptake. However, elevated myoplasmic [Ca2+] may also activate RyRs and promote stochastic SR Ca2+ release, which can in turn decrease SR [Ca2+]. Increasing myoplasmic [Ca2+] results in an exponential increase in spark-mediated release and a linear increase in nonspark-mediated release, consistent with recent experiments. The model exhibits two steady-state release fluxes for the same network SR [Ca2+] depending on whether myoplasmic [Ca2+] is low or high. In the later case, spontaneous release decreases SR [Ca2+] in a manner that maintains robust Ca2+ sparks.
Recommended Citation
Wang, Xiao; Weinberg, Seth H.; Smith, Gregory D.; Hao, Yan; and Sobie, Eric A., Calcium Homeostasis in a Local/Global Whole Cell Model of Permeabilized Ventricular Myocytes with a Langevin Description of Stochastic Calcium Release (2015). American Journal of Physiology-Heart and Circulatory Physiology, 308(5), H510-H523.
https://doi.org/10.1152/ajpheart.00296.2014
DOI
https://doi.org/10.1152/ajpheart.00296.2014