Activity-dependent neurotransmitter release kinetics: correlation with changes in morphological distributions of small and large vesicles in central nerve terminals.

In central nerve terminals transmitter release is tightly regulated and thought to occur in a number of steps. These steps include vesicle mobilization and docking prior to neurotransmitter release. Intrasynaptic changes in vesicle distribution were determined by electron microscopical analysis and neurotransmitter release was monitored by biochemical measurements. We correlated K + -induced changes in distribution of small and large vesicles with the release of their transmitters. For small synaptic vesicles, amino acid release as well as recruitment to and docking at the active zone were activated within 1 s of depolarization. In contrast, the disappearance of large dense-cored vesicles and the release of the neuropeptide cholecystokinin were much slower, and no docking was observed. Studies with diverse Ca2 + channel blockers indicated that mobilization and neurotransmitter release from both vesicle types were regulated by multiple Ca2 + channels, although in different ways. Neurotransmitter release from small synaptic vesicles was predominantly regulated by P-type Ca2 + channels, whereas primarily Q-type Ca2 + channels regulated neurotransmitter release from large dense-cored vesicles. The different Ca2 + channnel types directly regulated mobilization of and neurotransmitter release from small synaptic vesicles whereas, by their cooperativity in raising the intracellular Ca2 + concentration above release threshold, they more indirectly regulated large dense-cored vesicle exocytosis.