Release of neurotransmitter induced by Ca²⁺-uncaging: Reexamination of the Ca-voltage hypothesis for release

The primacy of Ca²⁺ in controlling the amount of released neurotransmitter is well established. However, it is not yet clear what controls the time-course (initiation and termination) of release. Various experiments indicated that the time-course is controlled by membrane potential per se. Consequently the phenomenological Ca-Voltage-Hypothesis (CVH) was formulated. The CVH was later embodied in a molecular level mathematical model, whose key predictions were affirmed experimentally. Nonetheless, the single most important basis for the CVH, namely that depolarization per se is needed to induce physiological phasic release, was challenged by two major experimental findings. (i) Release was induced by Ca²⁺ alone by means of Ca²⁺-uncaging. (ii) There was at most a small additional effect when depolarization was applied after release was induced by Ca²⁺-uncaging. Point (i) was dealt with previously, but additional conclusions are drawn here. Here we concentrate on (ii) and show that the experimental results can be fully accounted for by the molecular level CVH model, with essentially the same parameters.