Ganong's Review of Medical Physiology, 23rd Edition

CLINICAL BOX 7–1
Excitotoxins
Glutamate is usually cleared from the brain’s extracellular
fluid by Na + -dependent uptake systems in neurons and
glia, keeping only micromolar levels of the chemical in the
extracellular fluid despite millimolar levels inside neurons.
However, excessive levels of glutamate occur in response
to ischemia, anoxia, hypoglycemia, or trauma. Glutamate
and some of its synthetic congeners are unique in that
when they act on neuronal cell bodies, they can produce so
much Ca 2+ influx that neurons die. This is the reason why
microinjection of these excitotoxins is used in research to
produce discrete lesions that destroy neuronal cell bodies
without affecting neighboring axons. Evidence is accumulating
that excitotoxins play a significant role in the damage
done to the brain by a stroke. When a cerebral artery is
occluded, the cells in the severely ischemic area die. Surrounding
partially ischemic cells may survive but lose their
ability to maintain the transmembrane Na + gradient. The
elevated levels of intracellular Na + prevent the ability of astrocytes
to remove glutamate from the brain’s extracellular
fluid. Therefore, glutamate accumulates to the point
that excitotoxic damage and cell death occurs in the penumbra,
the region around the completely infarcted area.
nerve endings. Acetylcholine is then taken up into synaptic
vesicles by a vesicular transporter, VAChT.
Cholinesterases
Acetylcholine must be rapidly removed from the synapse if repolarization
is to occur. The removal occurs by way of hydrolysis
of acetylcholine to choline and acetate, a reaction catalyzed
by the enzyme acetylcholinesterase. This enzyme is also called
true or specific cholinesterase. Its greatest affinity is for acetylcholine,
but it also hydrolyzes other choline esters. There are a
variety of esterases in the body. One found in plasma is capable
of hydrolyzing acetylcholine but has different properties from
acetylcholinesterase. It is therefore called pseudocholinesterase
or nonspecific cholinesterase. The plasma moiety is
partly under endocrine control and is affected by variations in
liver function. On the other hand, the specific cholinesterase
molecules are clustered in the postsynaptic membrane of cholinergic
synapses. Hydrolysis of acetylcholine by this enzyme is
rapid enough to explain the observed changes in Na + conductance
and electrical activity during synaptic transmission.
Acetylcholine Receptors
Historically, acetylcholine receptors have been divided into
two main types on the basis of their pharmacologic properties.
Muscarine, the alkaloid responsible for the toxicity of
CHAPTER 7 Neurotransmitters & Neuromodulators 135
ACh
Cholinergic
neuron
Acetyl-CoA
+
Choline
ACh
Postsynaptic
tissue
Choline
ASE
FIGURE 7–4 Biochemical events at cholinergic endings. ACh,
acetylcholine; ASE, acetylcholinesterase; X, receptor.
toadstools, has little effect on the receptors in autonomic ganglia
but mimics the stimulatory action of acetylcholine on
smooth muscle and glands. These actions of acetylcholine are
therefore called muscarinic actions, and the receptors involved
are muscarinic cholinergic receptors. They are
blocked by the drug atropine. In sympathetic ganglia, small
amounts of acetylcholine stimulate postganglionic neurons
and large amounts block transmission of impulses from
preganglionic to postganglionic neurons. These actions are
unaffected by atropine but mimicked by nicotine. Consequently,
these actions of acetylcholine are nicotinic actions
and the receptors are nicotinic cholinergic receptors. Nicotinic
receptors are subdivided into those found in muscle at
neuromuscular junctions and those found in autonomic ganglia
and the central nervous system. Both muscarinic and nicotinic
acetylcholine receptors are found in large numbers in
the brain.
The nicotinic acetylcholine receptors are members of a
superfamily of ligand-gated ion channels that also includes the
GABA A and glycine receptors and some of the glutamate
receptors. They are made up of multiple subunits coded by different
genes. Each nicotinic cholinergic receptor is made up of
five subunits that form a central channel which, when the
receptor is activated, permits the passage of Na + and other cations.
The 5 subunits come from a menu of 16 known subunits,
α 1 –α 9 , β 2 –β 5 , γ, δ, and ε, coded by 16 different genes. Some of
the receptors are homomeric—for example, those that contain
five α 7 subunits—but most are heteromeric. The muscle type
nicotinic receptor found in the fetus is made up of two α 1 subunits,
a β 1 subunit, a γ subunit, and a δ subunit (Figure 7–5).
In adult mammals, the γ subunit is replaced by a δ subunit,
which decreases the channel open time but increases its