Modeling Study of the Effects of Membrane Surface Charge on Calcium Microdomains and Neurotransmitter Release

Synchronous neurotransmitter release is mediated by the opening of voltage-gated Ca2+ channels and the build-up of submembrane Ca2+ microdomains. Previous models of Ca2+ microdomains have neglected possible electrostatic interactions between Ca2+ ions and negative surface charges on the inner leaflet of the plasma membrane. To address the effects of these interactions, we built a computational model of ion electrodiffusion described by the Nernst-Planck and Poisson equations. We found that inclusion of a negative surface charge significantly alters the spatial characteristics of Ca2+ microdomains. Specifically, close to the membrane, Ca2+ ions accumulate, as expected from the strong electrostatic attraction exerted on positively charged Ca2+ ions. Farther away from the membrane, increasing the surface charge density results in a reduction of the Ca2+ concentration because of the preferential spread of Ca2+ ions along lateral directions. The model also predicts that the negative surface charge will decrease the spatial gradient of the Ca2+ microdomain in the lateral direction, resulting in increased overlap of microdomains originating from different Ca2+ channels. Finally, we found that surface charge increases the probability of vesicle release if the Ca2+ sensor is located within the electrical double layer, whereas this probability is decreased if the Ca2+ sensor lies at greater distances from the membrane. Our data suggest that membrane surface charges exert a significant influence on the profile of Ca2+ microdomains, and should be taken into account in models of neurotransmitter release.