Consequences of molecular-level Ca2+ channel and synaptic vesicle colocalization for the Ca2+ microdomain and...

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.