Figure 13–67 Exocytosis of synaptic vesicles. for orientation at a synapse, see figure 11–36. (a) The trans-snare complex responsible for docking synaptic vesicles at the plasma membrane of nerve terminals consists of three proteins. The v-snare synaptobrevin and the t-snare syntaxin are both transmembrane proteins, and each contributes one α helix to the complex. by contrast to other snares discussed earlier, the t-snare snaP25 is a peripheral membrane protein that contributes two α helices to the four-helix bundle; the two helices are connected by a loop (dashed line) that lies parallel to the membrane and has fatty acyl chains (not shown) attached to anchor it there. The four α helices are shown as rods for simplicity. (b) at the synapse, the basic snare machinery is modulated by the ca2+ sensor synaptotagmin and an additional protein called complexin. synaptic vesicles first dock at the membrane (step 1), and the snare bundle partially assembles (step 2), resulting in a “primed vesicle” that is already drawn close to the membrane. The snare bundle assembles further but the additional binding of complexin prevents fusion (step 3). upon arrival of an action potential, ca2+ enters the cell and binds to synaptotagmin, which releases the block and opens a fusion pore (step 4). further rearrangements complete the fusion reaction (step 5) and release the fusion machinery, which now can be reused. This elaborate arrangement allows the fusion machinery to respond on the millisecond time scale essential for rapid and repetitive synaptic signaling. (a, adapted from r.b. sutton et al., nature 395:347–353, 1998. with permission from Macmillan publishers ltd.; b, adapted from Z.p. pang and T.c. südhof, Curr. Opin. Cell Biol. 22:496–505, 2010. with permission from elsevier.) diameter) secretory vesicles called synaptic vesicles. These vesicles store small neurotransmitter molecules, such as acetylcholine, glutamate, glycine, and γ-aminobutyric acid (GABA), which mediate rapid signaling from nerve cell to its target cell at chemical synapses. When an action potential arrives at a nerve terminal, it causes an influx of Ca2+ through voltage-gated Ca2+ channels, which triggers the synaptic vesicles to fuse with the plasma membrane and release their contents to the extracellular space (see Figure 11–36). Some neurons fire more than 1000 times per second, releasing neurotransmitters each time.
The speed of transmitter release (taking only milliseconds) indicates that the proteins mediating the fusion reaction do not undergo complex, multistep rearrangements. Rather, after vesicles have been docked at the presynaptic plasma membrane, they undergo a priming step, which prepares them for rapid fusion. In the primed state, the SNAREs are partly paired, their helices are not fully wound into the final four-helix bundle required for fusion (Figure 13–67). Proteins called complexins freeze the SNARE complexes in this metastable state. The brake imposed by the complexins is released by another synaptic vesicle protein, synaptotagmin, which contains Ca2+-binding domains. A rise in cytosolic Ca2+ triggers binding of synaptotagmin to phospholipids and to the SNAREs, displacing the complexins. As the SNARE bundle zippers up completely, a fusion pore opens and the neurotransmitters are released. At a typical synapse, only a small number of the docked vesicles are primed and ready for exocytosis. The use of only a small number of vesicles at a time allows each synapse to fire over and over again in quick succession. With each firing, new synaptic vesicles dock and become primed to replace those that have fused and released their contents.