Synaptic Vesicles and Recycling
There seem to be two pools of vesicles that release acetylcholine,
a readily releasable store and a reserve store, sometimes called VP2 and VP1, respectively.
[25]
[29]
The vesicles
in the former are a bit smaller and are limited to an area very close to the nerve
membrane, where they probably are bound to the active zones. These vesicles are
the ones that ordinarily release transmitter. The release seems to occur when calcium
ion enters the nerve through the P channels lined up on the sides of the active zones.
[29]
This calcium needs to move only a very short
distance (i.e., a few atomic radii) to encounter a vesicle and to activate the proteins
in the vesicle wall involved in a process known as docking[30]
(see "Process of Exocytosis"). The activated protein seems to react with the nerve
membrane to form a pore, through which the vesicle discharges its acetylcholine into
the junctional cleft. Studies using fluorescent proteins have visualized how synaptic
vesicles fuse with release sites and release their contents, which are then retrieved.
[31]
Some vesicles stay open briefly before retrieval
and do not completely collapse into the surface membrane ("kiss and run"). Others
stay open longer and probably do not completely collapse ("compensatory"). Still
others completely collapse and are not retrieved until another stimulus is delivered
("stranded").[31]
Most vesicles in the nerve ending are the larger reserve (VPI)
vesicles. These are firmly tethered to the cytoskeleton by many proteins, including
actin, synapsin (an actinbinding protein), and spectrin.[32]
From their position on the cytoskeleton, they may be moved to the readily releasable
store to replace worn-out vesicles or to participate in transmission when the nerve
is called on to work especially hard (e.g., when it is stimulated at very high frequencies
or for a very long time). Under such strenuous circumstances, calcium may penetrate
more deeply than normal into the nerve or may enter through L channels to activate
calcium-dependent enzymes, which cause breakage of the synapsin links that hold the
vesicles to the cytoskeleton, thereby allowing the vesicles to be moved to the release
sites. Repeated stimulation requires the nerve ending to replenish its stores of
vesicles filled with transmitter, a process known as mobilization. The term commonly
is applied to the aggregate of all steps involved in maintaining the nerve ending's
capacity to release transmitter—everything from the acquisition of choline
and the synthesis of acetate to the movement of filled vesicles to the release sites.
The uptake of choline and the activity of choline acetyltransferase, the enzyme
that synthesizes acetylcholine, probably are the rate-limiting steps.[10]
[11]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
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