Quantal Theory
The contents of the nerve ending are not homogeneous. As shown
in Figure 22-1
, the vesicles
are congregated in the portion toward the junctional surface, whereas the microtubules,
mitochondria, and other support structures are located toward the opposite side.
The vesicles containing transmitter are ordered in repeating clusters alongside
small, thickened, electron-dense patches of membrane, referred to as active
zones or release sites. This thickened
area is a cross section of a band running across the width of the synaptic surface
of the nerve ending, believed to be the structure to which vesicles attach (active
zones) before they rupture into the junctional cleft (see "Process of Exocytosis").
High-resolution scanning electron micrographs reveal small protein particles arranged
alongside the active zone between vesicles. These particles are believed to be special
channels, the voltage-gated calcium channels, that allow calcium to enter the nerve
and cause the release of vesicles.[21]
The rapidity
with which the neurotransmitter is released (200 µsec) suggests that the voltage-gated
calcium channels are close to the release sites.
When observing the electrophysiologic activity of a skeletal muscle,
small, spontaneous, depolarizing potentials at neuromuscular junctions can be seen.
These potentials have only one-hundredth the amplitude of the
evoked end-plate potential produced when the motor nerve is stimulated. Except for
amplitude, these potentials resemble the end-plate potential in the time course and
the manner in which they are affected by drugs. These small-amplitude potentials
are called miniature end-plate potentials (MEPPs).
Statistical analysis led to the conclusion that they are unitary responses; that
is, there is a minimum size for the MEPP, and the sizes of all MEPPs are equal to
or multiples of this minimum size. Because MEPPs are too big to be produced by a
single molecule of acetylcholine, it was deduced that they are produced by uniformly
sized packages, or quanta, of transmitter released
from the nerve (in the absence of stimulation). The stimulus-evoked end-plate potential
is the additive depolarization produced by the synchronous discharge of quanta from
several hundred vesicles. The action potential that is propagated to the nerve ending
allows entry of calcium into the nerve through voltage-gated calcium channels, and
this causes vesicles to migrate to the active zone, fuse with the neural membrane,
and discharge their acetylcholine into the junctional cleft.[21]
[22]
Because the release sites are located immediately
opposite the receptors on the postjunctional surface, little transmitter is wasted,
and the response of the muscle is coupled directly with the signal from the nerve.
The alignment of the presynaptic receptor site is achieved by
adhesion molecules or specific cell-surface proteins located on both sides of the
synapse that grip each other across the synaptic cleft and hold the prejunctional
and postjunctional synaptic apparatuses together.[23]
One such protein implicated in synapse adhesion is neurexin, which binds to neuroligins
on the postsynaptic membrane. The amount of acetylcholine released by each nerve
impulse is large, at least 200 quanta of about 5000 molecules each, and the number
of acetylcholine receptors activated by transmitter released by a nerve impulse also
is large, about 500,000. The ions (mostly Na+
and some Ca2+
)
that flow through the channels of the activated receptors cause a maximum depolarization
of the end plate, which causes an end-plate potential that is greater than the threshold
for stimulation of the muscle. This is a very vigorous system. The signal is carried
by more molecules of transmitter than are needed, and they evoke a response that
is greater than needed. At the same time, only a small fraction of the available
vesicles and receptors or channels are used to send each signal. Consequently, transmission
has a substantial margin of safety, and at the same time, the system has substantial
capacity in reserve.[24]
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