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Consequences of Molecular-Level Ca²⁺ Channel and Synaptic Vesicle Colocalization for the Ca²⁺ Microdomain and Neurotransmitter Exocytosis: A Monte Carlo Study

Vahid Shahrezaei ^* and Kerry R. Delaney 

Departments of ^* Physics and Biological Sciences, Simon Fraser University, Burnaby, British Columbia, Canada

Correspondence: Address reprint requests to V. Shahrezaei, Department of Physics, Simon Fraser University, 8888 University Dr., Burnaby, BC, Canada V5A 1S6. Tel.: 604-291-4395; Fax: 604-291-3592; E-mail: vshahrez{at}sfu.ca.

Morphological and biochemical studies indicate association between voltage-gated Ca²⁺ channels and the vesicle docking complex at vertebrate presynaptic active zones, which constrain the separation between some Ca²⁺ channels and vesicles to 20 nm or less. To address the effect of the precise geometrical relationship among the vesicles, the Ca²⁺ channel, and the proteins of the release machinery on neurotransmitter release, we developed a Monte Carlo simulation of Ca²⁺ diffusion and buffering with nanometer resolution. We find that the presence of a vesicle as a diffusion barrier alters the shape of the Ca²⁺ microdomain of a single Ca²⁺ channel around the vesicle. This effect is maximal in the vicinity of the vesicle and depends critically on the vesicle's distance from the plasmalemma. Ca²⁺-sensor(s) for release would be exposed to markedly different [Ca²⁺], varying by up to 13-fold, depending on their position around the vesicle. As a result, the precise position of Ca²⁺-sensor(s) with respect to the vesicle and the channel can be critical to determining the release probability. Variation in the position of Ca²⁺-sensor molecule(s) and their accessibility could be an important source of heterogeneity in vesicle release probability.

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