Neurotransmitter release at fast synapses.

As stated at the beginning of this review, the mechanism of neurotransmitter release is not yet known. Keeping this in mind, we shall, nevertheless, attempt to speculate and outline a possible scenario of events as it emerges from the foregoing discussion. At resting membrane potentials, the release machinery is in a blocked state produced by the constant presence in the synaptic cleft of neurotransmitter at low concentrations. At resting potentials, Ca2+ channels are closed, but this is probably not associated with the presence of low levels of neurotransmitter. Upon arrival of the action potential at the nerve terminal, (as suggested by the Ca-voltage hypothesis) two things happen independently: The release machinery is relieved of its block, being activated and readied to trigger release. Concurrently, Ca2+ enters the presynaptic terminal, and together with specific Ca2+ binding proteins, it abolishes the hydration repulsive forces without which the intimate contact between the vesicle and the plasmatic release machinery is not possible. The biophysical meaning of triggering release is at present not known. There are several suggestions, the one most consistent with the arguments of this review being the mechanism discussed and modeled by Nanavati et al. (1992; see also review: Monck & Fernandez, 1992). According to that hypothesis, an activated scaffold of proteins forms a dimple in the plasma membrane upon stimulation. This dimple, which exhibits high tension--perhaps together with Ca(2+)--overcomes the repulsive forces of hydration, permitting the two membranes to "jump" into intimate contact. As a result, a single hemifused bilayer is formed. In this hemifused bilayer, a lipidic fusion pore opens. In the context of the lipidic fusion pore hypothesis, the role of the depolarization-dependent triggering could be to start those manipulations in the plasmatic membrane that result in increased lateral bilayer tension and formation of the dimple. Ca2+ could then, in view of reduced repulsive forces and increased attractive forces, be responsible for the intimate docking of the vesicle at the release site. Under such conditions, hemifusion could take place with the final formation of the lipidic fusion pore. Finally, once the fusion pore opens, discharge of the vesicular content takes place immediately and lasts for up to 50-70 microseconds. To be so fast, discharge must occur by a mechanism other than diffusion, possibly by ion-exchange (R. Khanin, H. Parnas and L. Segel, in preparation).(ABSTRACT TRUNCATED AT 400 WORDS)