Calcium release site ultrastructure and the dynamics of puffs and sparks.
When Markov chain models of intracellular Ca(2+)-regulated Ca(2+) channels are coupled via a mathematical representation of a Ca(2+) microdomain, simulated Ca(2+) release sites may exhibit the phenomenon of 'stochastic Ca(2+) excitability' reminiscent of Ca(2+) puffs and sparks. Interestingly, some single-channel models that include Ca(2+) inactivation are not particularly sensitive to channel density, so long as the requirement for inter-channel communication is satisfied, while other single-channel models that do not include Ca(2+) inactivation open and close synchronously only when the channel density is in a prescribed range. This observation led us to hypothesize that single-channel models with Ca(2+) inactivation would be less sensitive to the details of release site ultrastructure than models that lack a slow Ca(2+) inactivation process. To determine if this was the case, we simulated Ca(2+) release sites composed of instantaneously coupled Ca(2+)-regulated Ca(2+) channels whose random spatial locations were chosen from a uniform distribution on a disc of specified radius and compared the resulting release site dynamics to simulations with channels arranged on hexagonal lattices. Analysis of puff/spark statistics confirmed our hypothesis that puffs and sparks are less sensitive to the spatial organization of release sites when the single-channel model includes a slow inactivation process. We also investigated the validity of several different mean-field reductions that do not explicitly account for the details of release site ultrastructure. The most successful approximation maintains a distinction between each channel's substantial influence on its own stochastic gating and the collective contribution of elevated [Ca(2+)] from neighbouring channels.
DeRemigio
Hilary
H
Department of Applied Science, The College of William and Mary, Williamsburg, VA 23187, USA.
Groff
Jeffrey R
JR
Smith
Gregory D
GD
D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D003198:Computer Simulation; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D008390:Markov Chains; D008954:Models, Biological; D015233:Models, Statistical; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D013269:Stochastic Processes
D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium