Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

TRANSPORT FROM THE TRANS GOLGI NETWORK TO THE CELL EXTERIOR: EXOCYTOSIS
745
v-SNARE
(synaptobrevin)
LUMEN OF
SYNAPTIC
VESICLE
CYTOSOL
t-SNARE
(SNAP25)
synaptotagmin
synaptic
vesicle
Ca 2+ -binding sites
synaptobrevin
t-SNARE
(syntaxin)
syntaxin
SNAP25
(A)
presynaptic
plasma membrane
SYNAPTIC CLEFT
(B) 1. DOCKING presynaptic
2. PRIMING I partially
plasma membrane
assembled
SNARE bundle
Ca 2+
complexin
5. FUSION COMPLETE
released
neurotransmitter
4. FUSION PORE OPENING
3. PRIMING II
complexinblocked
SNARE bundle
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 MBoC6 both n13.500/13.68
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 Ca 2+ 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, Ca 2+ 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 Ca 2+ through voltage-gated Ca 2+ 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 Ca 2+ -binding domains. A rise in cytosolic Ca 2+
triggers binding of synaptotagmin to phospholipids and to the SNAREs, displacing
the complexins. As the SNARE bundle zippers up completely, a fusion pore