Modeling study of exocytosis in neuroendocrine cells: influence of the geometrical parameters.

Exocytosis in neuroendocrine cells is a process triggered by Ca(2+). A Monte Carlo simulation of secretion has been developed which, together with the diffusion of calcium, buffered by endogenous and/or exogenously added chelators, also accounts for the dynamics of exocytosis for a pool of readily releasable vesicles. Different distributions of channels and vesicles (random or correlated) are studied. A local study of exocytosis is carried out by obtaining capacitance time courses for the different types of release-ready vesicle pools (correlated or not with Ca(2+) channels). Also, depending upon the kinetic constants for the exocytotic process, we study the levels of local Ca(2+) needed to trigger secretion. Our simulations show that a strong heterogeneity in the calcium concentrations at the different sites of exocytosis is a requirement for reproducing the experimentally observed biphasic response in chromaffin cells in situ (Voets, T., E. Neher, and T. Moser. 1999. Neuron. 23:607-615). Correlated nonuniform distributions of channels and vesicles and the existence of diffusion barriers are shown to quantitatively explain the experimental data on chromaffin cells in situ. The first description requires a deeply heterogeneous distribution, with vesicles attached to the channels or far from them, but never at middle distances. The second description is able to reproduce biphasic release even for uniformly (readily releasable) distributed vesicles. We quantify the degree of inhomogeneity in the distribution of vesicles and how porous the diffusion barriers should be to account for the observed biphasic response.