Process of Exocytosis
The readily releasable pool of synaptic vesicles constitutes those
vesicles readily available for release. During an action potential and calcium influx,
neurotransmitter is released. Studies have shed some light on the inner workings
by which the vesicle releases its contents. A conserved set of membrane proteins
known as SNAREs
Figure 22-3
Model for protein-mediated membrane fusion and exocytosis.
A, The release of acetylcholine from the vesicles
is mediated by a series of proteins collectively called SNARE proteins. Synaptotagmin
is the neuronal Ca2+
receptor detecting Ca2+
entry. Synaptobrevin
(i.e., vesicle-associated membrane protein [VAMP]) is a filament-like protein on
the vesicle. B, During depolarization and calcium
entry, synaptobrevin on the vesicle unfolds and forms a ternary complex with syntaxin/SNAP-25.
This process is facilitated by phosphorylation of synapsin, also present on the
vesicle membrane. C, Assembly of the ternary complex
forces the vesicle in close apposition to the nerve membrane at the active zone with
release of its contents, acetylcholine. The fusion is disassembled, and the vesicle
is recycled.
(soluble N-ethylmaleimide-sensitive attachment protein
receptors) are involved in the fusion, docking, and release of acetylcholine at the
active zone. The whole process is called exocytosis.
The SNAREs include the synaptic-vesicle protein synaptobrevin and the plasmalemma-associated
proteins synataxin and synaptosome-associated protein of 25 kd (SNAP-25).[33]
The current model for protein-mediated membrane fusions in exocytosis is as follows.
Syntaxin and SNAP-25 are complexes attached to plasma membrane. After initial contact,
the synaptobrevin on the vesicle forms a ternary complex with syntaxin/SNAP-25.
Synaptotagmin is the protein on the vesicular membrane that acts as a calcium sensor
and localizes the synaptic vesicles to synaptic zones rich in calcium channels, stabilizing
the vesicles in the docked state.[34]
The assembly
of ternary complex forces the vesicle close to the underlying nerve terminal membrane
(i.e., active zone), and the vesicle is then ready for release ( Fig.
22-3
). The vesicle can release part or all of its contents, some of which
can be recycled to form new vesicles.[31]
Botulinum
toxin and tetanus neurotoxins, which selectively digest one or all of these three
SNARE proteins, blocks exocytosis.[35]
The result
is muscle weakness or paralysis. These toxins in effect produce a partial or complete
chemical denervation. Botulinum toxin is used therapeutically to treat spasticity
or spasm in several neurologic and surgical diseases and cosmetically to correct
wrinkles.
