Spontaneous Ca2+ sparks and Ca2+ homeostasis in a minimal model of permeabilized ventricular myocytes.
Many issues remain unresolved concerning how local, subcellular Ca(2+) signals interact with bulk cellular concentrations to maintain homeostasis in health and disease. To aid in the interpretation of data obtained in quiescent ventricular myocytes, we present here a minimal whole cell model that accounts for both localized (subcellular) and global (cellular) aspects of Ca(2+) signaling. Using a minimal formulation of the distribution of local [Ca(2+)] associated with a large number of Ca(2+)-release sites, the model simulates both random spontaneous Ca(2+) sparks and the changes in myoplasmic and sarcoplasmic reticulum (SR) [Ca(2+)] that result from the balance between stochastic release and reuptake into the SR. Ca(2+)-release sites are composed of clusters of two-state ryanodine receptors (RyRs) that exhibit activation by local cytosolic [Ca(2+)] but no inactivation or regulation by luminal Ca(2+). Decreasing RyR open probability in the model causes a decrease in aggregate release flux and an increase in SR [Ca(2+)], regardless of whether RyR inhibition is mediated by a decrease in RyR open dwell time or an increase in RyR closed dwell time. The same balance of stochastic release and reuptake can be achieved, however, by either high-frequency/short-duration or low-frequency/long-duration Ca(2+) sparks. The results are well correlated with recent experimental observations using pharmacological RyR inhibitors and clarify those aspects of the release-reuptake balance that are inherent to the coupling between local and global Ca(2+) signals and those aspects that depend on molecular-level details. The model of Ca(2+) sparks and homeostasis presented here can be a useful tool for understanding changes in cardiac Ca(2+ )release resulting from drugs, mutations, or acquired diseases.
Hartman
Jana M
JM
Department of Applied Science, The College of William and Mary, Williamsburg, Virginia 23187, USA.
Sobie
Eric A
EA
Smith
Gregory D
GD
D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002463:Cell Membrane Permeability; D003198:Computer Simulation; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D015640:Ion Channel Gating; D008390:Markov Chains; D008564:Membrane Potentials; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013269:Stochastic Processes; D013748:Tetracaine / Q000494:pharmacology; D013997:Time Factors
D000779:Anesthetics, Local; D019837:Ryanodine Receptor Calcium Release Channel; D013748:Tetracaine; D002118:Calcium