Neuronal Signaling and the Structure of the Nervous System
167
Acetylcholine (ACh) is synthesized from choline and
acetyl coenzyme A in the cytoplasm of synaptic terminals,
and stored in synaptic vesicles. After it is released and acti-
vates receptors on the postsynaptic membrane, the concentra-
tion of ACh at the postsynaptic membrane decreases (thereby
stopping receptor activation) due to the action of the enzyme
acetylcholinesterase.
This enzyme is located on the pre- and
postsynaptic membranes and rapidly destroys ACh, releas-
ing choline and acetate. The choline is then transported back
into the presynaptic axon terminals where it is reused in the
synthesis of new ACh. The ACh concentration at the recep-
tors is also reduced by simple diffusion away from the synapse
and eventual breakdown of the molecule by an enzyme in the
blood. Some chemical weapons, such as the nerve gas
Sarin,
inhibit acetylcholinesterase, causing a buildup of ACh in the
synaptic cleft. This results in overstimulation of postsynaptic
ACh receptors, initially causing uncontrolled muscle contrac-
tions, but ultimately leading to receptor desensitization and
paralysis.
There are two types of ACh receptors, and they are dis-
tinguished by their responsiveness to two different drugs.
Recall that although a receptor is considered specifi c for a given
ligand, such as ACh, most receptors will recognize natural
or synthetic compounds that exhibit some degree of chemi-
cal similarity to that ligand. Some ACh receptors respond not
only to acetylcholine but to the drug nicotine, and have there-
fore come to be known as
nicotinic receptors.
The nicotinic
receptor is an excellent example of a receptor that contains
an ion channel (i.e., a ligand-gated channel); in this case the
channel is permeable to both sodium and potassium ions.
Nicotinic receptors are present at the neuromuscular junc-
tion and, as Chapter 9 will explain, several nicotinic receptor
antagonists are toxins that induce paralysis. Nicotinic receptors
in the brain are important in cognitive functions and behavior.
Their presence on presynaptic terminals in reward pathways of
the brain suggest an explanation for why tobacco use is addic-
tive. As another example, one cholinergic system that employs
nicotinic receptors plays a major role in attention, learning,
and memory by reinforcing the ability to detect and respond
to meaningful stimuli.
Neurons associated with the ACh system degenerate in
people with
Alzheimer’s disease,
a brain disease that is usually
age-related and is the most common cause of declining intel-
lectual function in late life. Alzheimer’s disease affects 10 to 15
percent of people over age 65, and 50 percent of people over age
85. Because of the degeneration of cholinergic neurons, this
disease is associated with a decreased amount of ACh in certain
areas of the brain and even the loss of the postsynaptic neurons
that would have responded to it. These defects and those in
other neurotransmitter systems that are affected in this disease
are related to the declining language and perceptual abilities,
confusion, and memory loss that characterize Alzheimer’s vic-
tims. The exact causes of this degeneration are unknown.
The other type of cholinergic receptor is stimulated not
only by acetylcholine but by the mushroom poison musca-
rine; therefore, these are called
muscarinic receptors.
These
receptors couple with G proteins, which then alter the activity
of a number of different enzymes and ion channels. They are
prevalent at cholinergic synapses in the brain and at junctions
of neurons that innervate many glands and organs, notably
the heart.
Atropine
is an antagonist of muscarinic receptors
with many clinical uses, such as in eye drops that dilate the
pupils for an eye exam.
Biogenic Amines
The
biogenic amines
are small, charged molecules that are
synthesized from amino acids and contain an amino group
(R—NH
2
). The most common biogenic amines are dopa-
mine, norepinephrine, serotonin, and histamine. Epinephrine,
another biogenic amine, is not a common neurotransmitter in
the central nervous system but is the major
hormone
the adre-
nal medulla secretes. Norepinephrine is an important neu-
rotransmitter in both the central and peripheral components
of the nervous system.
Catecholamines
Dopamine,
norepinephrine (NE),
and
epinephrine
all
contain a catechol ring (a six-carbon ring with two adjacent
hydroxyl groups) and an amine group; thus they are called
cat-
echolamines.
The catecholamines are formed from the amino
acid tyrosine and share the same two initial steps in their syn-
thetic pathway (
Figure 6–35
). Synthesis of catecholamines
begins with the uptake of tyrosine by the axon terminals and
its conversion to another precursor, L-dihydroxy-phenylalanine
(
L-dopa
) by the rate-limiting enzyme in the pathway, tyrosine
hydroxylase. Depending on the enzymes present in the termi-
nals, any one of the three catecholamines may ultimately be
Table 6–6
Classes of Some of the Chemicals
Known or Presumed to Be
Neurotransmitters or Neuromodulators
1. Acetylcholine (ACh)
2. Biogenic amines
Catecholamines
Dopamine (DA)
Norepinephrine (NE)
Epinephrine (Epi)
Serotonin (5-hydroxytryptamine, 5-HT)
Histamine
3. Amino acids
Excitatory amino acids; for example, glutamate
Inhibitory amino acids; for example, gamma-
aminobutyric acid (GABA) and glycine
4. Neuropeptides
For example, endogenous opioids, oxytocin, tachykinins
5. Miscellaneous
Gases; for example, nitric oxide
Purines; for example, adenosine and ATP
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