Neuronal Signaling and the Structure of the Nervous System
161
at release regions known as
active zones,
while others are dis-
persed within the terminal. Neurotransmitter release is initiated
when an action potential reaches the terminal of the presynap-
tic membrane. A key feature of neuron terminals is that in addi-
tion to the sodium and potassium channels found elsewhere in
the neuron, they also possess voltage-gated calcium channels.
Depolarization during the action potential opens these calcium
channels, and because the electrochemical gradient favors cal-
cium infl ux, calcium fl ows into the axon terminal.
Calcium activates processes that lead to the fusion of
docked vesicles with the synaptic terminal membrane (
Figure
6–27b
). Prior to the arrival of an action potential, vesicles
are loosely docked in the active zones by the interaction of a
group of proteins, some of which are anchored in the vesicle
membrane and others found in the membrane of the terminal.
These proteins are collectively known as
SNAREs
(soluble
N-ethylmaleimide-sensitive fusion protein attachment protein
receptors). Calcium entering during depolarization binds to a
separate family of proteins associated with the vesicle,
synap-
totagmins,
triggering a conformational change in the SNARE
complex that leads to membrane fusion and neurotransmitter
release.
Activation of the Postsynaptic Cell
Once neurotransmitters are released from the presynaptic
axon terminal, they diffuse across the cleft. A fraction of these
molecules bind to receptors on the plasma membrane of the
postsynaptic cell. The activated receptors themselves may be
ion channels, which designates them as
ionotropic receptors.
Alternatively, the receptors may act indirectly on separate ion
channels through a G protein and/or a second messenger, a
type referred to as
metabotropic receptors.
In either case,
the result of the binding of neurotransmitter to receptor is the
opening or closing of specifi c ion channels in the postsynaptic
plasma membrane, which eventually leads to functional changes
in that neuron. These channels belong, therefore, to the class of
ligand-gated channels controlled by receptors, as discussed in
Chapter 5, and are distinct from voltage-gated channels.
Because of the sequence of events involved, there is a very
brief
synaptic delay
—about 0.2 msec—between the arrival of
an action potential at a presynaptic terminal and the membrane
potential changes in the postsynaptic cell.
Neurotransmitter binding to the receptor is a tran-
sient event. As with any binding site, the bound ligand—in
this case, the neurotransmitter—is in equilibrium with the
unbound form. Thus, if the concentration of unbound neu-
rotransmitter in the synaptic cleft decreases, the number
of occupied receptors will decrease. The ion channels in the
postsynaptic membrane return to their resting state when the
neurotransmitter is no longer bound. Unbound neurotrans-
mitters are removed from the synaptic cleft when they (1) are
actively transported back into the presynaptic axon terminal
(in a process called
reuptake
) or, in some cases, into nearby
glial cells; (2) diffuse away from the receptor site; or (3) are
enzymatically transformed into inactive substances, some of
which are transported back into the axon terminal for reuse.
The two kinds of chemical synapses—excitatory and
inhibitory—are differentiated by the effects of the neurotrans-
mitter on the postsynaptic cell. Whether the effect is excitatory
or inhibitory depends on the type of signal transduction mecha-
nism brought into operation when the neurotransmitter binds
to a receptor and on the type of channel the receptor infl uences.
Excitatory Chemical Synapses
At an excitatory synapse, the postsynaptic response to the neu-
rotransmitter is a depolarization, bringing the membrane poten-
tial closer to threshold. The usual effect of the activated receptor
on the postsynaptic membrane at such synapses is to open non-
selective channels that are permeable to sodium, potassium, and
other small, positively charged ions. These ions then are free to
move according to the electrical and chemical gradients across
the membrane.
Action potential
reaches terminal
Voltage-gated Ca
2
+
channels open
Calcium enters
axon terminal
Axon terminal
Voltage-gated
Ca
2
+
channel
Synaptic
vesicles
1
2
3
Neurotransmitter
release and
diffusion
Neurotransmitter binds
to postsynaptic receptors
Neurotransmitter
removed from
synaptic cleft
Postsynaptic cell
Ca
2
+
4
5
6
Active
zone
Ca
2
+
(a)
(b)
+Ca
2
+
SNAREs
Synaptotagmin
Figure 6–27
(a) Neurotransmitter storage and release at the synapse and binding
to the postsynaptic receptor. Voltage-gated calcium channels in
the terminal open in response to an action potential, triggering
release of neurotransmitter. (b) Magnifi ed view showing details of
neurotransmitter release. Calcium entering the terminal binds to
synaptotagmin, stimulating SNARE proteins to induce membrane
fusion and neurotransmitter release.
Note:
The SNARE complex
is known to involve more proteins than are shown here. (SNARE =
Soluble N-ethylmaleimide-sensitive fusion protein attachment protein
receptor)
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