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 Ca2+ concentration ([Ca2+](o)), whereas the rate of release is highly [Ca2+](o)-dependent. Here, we examine the time course of release at inhibitory basket cell-Purkinje cell synapses and show that it is independent of [Ca2+](o). Modeling of Ca2+-dependent transmitter release suggests that the invariant time course of release critically depends on tight coupling between Ca2+ channels and release sensors. Experiments with exogenous Ca2+ 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 [Ca2+](o) independence of the time course of release.