Nanodomain coupling explains Ca²⁺ independence of transmitter release time course at a fast central synapse

A puzzling property of synaptic transmission, originally established at the neuromuscular junction, is that the time course of transmitter release is independent of the extracellular Ca(2+) concentration ([Ca(2+)]o), whereas the rate of release is highly [Ca(2+)]o-dependent. Here, we examine the time course of release at inhibitory basket cell-Purkinje cell synapses and show that it is independent of [Ca(2+)]o. Modeling of Ca(2+)-dependent transmitter release suggests that the invariant time course of release critically depends on tight coupling between Ca(2+) channels and release sensors. Experiments with exogenous Ca(2+) chelators reveal that channel-sensor coupling at basket cell-Purkinje cell synapses is very tight, with a mean distance of 10-20 nm. Thus, tight channel-sensor coupling provides a mechanistic explanation for the apparent [Ca(2+)]o independence of the time course of release.