Stochastic simulation of calcium microdomains in the vicinity of an L-type calcium channel

Abstract

We study numerically the local dynamics of the intracellular calcium concentration in the vicinity of a voltage- and calcium-dependent plasma membrane L-type calcium channel. To account for the low number of Ca(2+) ions and buffer molecules present in sub-femtoliter volumes, we use an exact stochastic simulation algorithm including diffusion. We present a novel, unified simulation method that implements reaction-diffusion events of Ca(2+) ions and buffer molecules, stochastic ion channel gating and channel conductance as a multivariate Markov process. For fixed-voltage dynamics, e.g. under voltage-clamp conditions, it is shown that voltage-sensitive channel-gating steps can be incorporated exactly. We compare multi- and single-voxel geometries and show that the single-voxel approach leads to almost identical first- and second-order moments, at much lower computation time. Numerical examples illustrate the variability in local Ca(2+) fluctuations as induced by bursts of channel openings in response to membrane depolarisations. Finally, by introducing calmodulin as a link, it is shown how this variability is passed on to downstream signalling pathways. The method may prove useful to study calcium microdomains and calcium-regulated processes triggered by membrane depolarisations as evoked by, e.g., viral channel-forming proteins during virus-host cell interactions.