The kinetics of nerve-evoked quantal secretion

Current views on quantal release of neurotransmitters hold that after the v esicle migrates towards release sites (active zones), multiple protein inte ractions mediate the docking of the vesicle to the presynaptic membrane and the formation of a multimolecular protein complex (the 'fusion machine') w hich ultimately makes the vesicle competent to release a quantum in respons e to the action potential. Classical biophysical studies of quantal release have modelled the process by a binomial system where n vesicles (sites) co mpetent for exocytosis release a quantum, with probability p, in response t o the action potential. This is likely to be an oversimplified model. Furth ermore, statistical and kinetic studies have given results which are diffic ult to reconcile within this framework. Here, data are presented and discus sed which suggest a revision of the biophysical model. Transient silencing of release is shown to occur following the pulse of synchronous transmitter release, which is evoked by the presynaptic action potential. This points to a schema where the vesicle fusion complex assembly is a reversible, stoc hastic process. Asynchronous exocytosis may occur at several intermediate s tages in the process, along paths which may be differentially regulated by divalent cations or other factors. The fusion complex becomes competent for synchronous release (armed vesicles) only at appropriately organized sites . The action potential then triggers (deterministically rather than stochas tically) the synchronous discharge of all armed vesicles. The existence of a specific conformation for the fusion complex to be competent for synchron ous evoked fusion reconciles statistical and kinetic results during repetit ive stimulation and helps explain the specific effects of toxins and geneti c manipulation on the synchronization of release in response to an action p otential.