On the slow track, vesicles are recruited from the reserve pool that corresponds to synaptic vesicles attached to the actin cytoskeleton via synapsin. These vesicles then translocate to the vicinity of the plasma membrane. They undergo priming through an unknown mechanism in which nSec1 and Munc13, two syntaxin-binding proteins, could participate. This step could lead to the formation of a complex between a synaptic vesicle SNARE (synaptobrevin) and SNAP-25, a plasma membrane target SNARE. Formation of loose SNARE complexes between synaptobrevin, SNAP-25 and syntaxin 1 reduces the distance between the synaptic vesicle and the plasma membrane. At this point, the synaptic vesicle would be docked to the plasma membrane. Entry of calcium could trigger a conformational change in synaptotagmin 1 that would allow further zippering of the SNARE complex into a tight state, which would lead to lipid bilayer fusion. The synaptic vesicle membranes would then disintegrate into the plasma membrane. The SNARE complexes, which have been inserted into the plasma membrane, are dissociated by the action of SNAPs (not shown for simplicity) and NSF. Synaptic vesicle proteins are then reinternalized by a clathrin- and dynamin-dependent mechanism at the plasma membrane or at the tip of endosome-like invaginations of the plasma membrane. Dynamin then catalyzes the fission of the emanating vesicle from the membrane. Free clathrin-coated vesicles are subsequently uncoated by hsp70, auxilin, and, possibly, synaptojanin. Finally, the proton pump restores the electrochemical gradient, allowing for the uptake of neurotransmitter into the vesicle. This last step leads to a reformed synaptic vesicle that can reenter the cycle.
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