Acetylcholinesterase
The acetylcholine released from the nerve diffuses across the
junctional cleft and reacts with specialized receptor proteins in the end plate to
initiate muscle contraction. Transmitter molecules that do not react immediately
with
a receptor or those released after binding to the receptor are destroyed almost instantly
by the acetylcholinesterase in the junctional cleft. Acetylcholinesterase at the
junction is the asymmetric or A12 form protein made in the muscle, under the end
plate. The acetylcholinesterase (enzyme classification 3.1.1.7) is a type-B carboxylesterase
enzyme. There is a smaller concentration of it in the extrajunctional area. The
enzyme is secreted from the muscle but remains attached to it by thin stalks of collagen
fastened to the basement membrane.[12]
[25]
Most of the molecules of acetylcholine released from the nerve initially pass between
the enzymes to reach the postjunctional receptors, but as they are released from
the receptors, they invariably encounter acetylcholinesterase and are destroyed.
Under normal circumstances, a molecule of acetylcholine reacts with only one receptor
before it is hydrolyzed. Acetylcholine is a potent messenger, but its actions are
very short lived because it is destroyed in less than 1 millisecond after it is released.
There are congenital and acquired diseases related to altered
activity of acetylcholinesterase enzyme. Congenital absence of the secreted enzyme
(in knock-out mice), leads to impaired maintenance of motor neuronal system and organization
of nerve terminal branches.[36]
Many syndromes
due to congenital abnormalities of cholinesterase enzymes have been described and
result in neuromuscular disorders whose symptoms and signs usually resemble those
of myasthenia.[37]
Denervation decreases the acetylcholinesterases
at the junctional and extrajunctional areas.[2]
Other acquired diseases of cholinesterases are related to chronic inhibition of
acetylcholinesterase by organophosphate pesticides or nerve gas (e.g., sarin) or
to chronic pyridostigmine therapy given as prophylaxis against nerve gas poisoning.
[38]
Symptoms from chronic fatigue to muscle weakness
have been attributed to chronic cholinesterase inhibition, underscoring the
Figure 22-4
Sketch of acetylcholine receptor channels (right)
and tracings of cell-patch records of receptor channel openings (left).
The mature, or junctional, receptor consists of two α-subunits and one each
of β-, δ, and epsilon-subunits. The immature, extrajunctional or fetal
form consists of two α- and one each of β, δ, and γ-subunits.
These subunits are arranged around the central cation channel. The immature isoform
containing the γ-subunit shows long open times and low-amplitude channel currents.
The mature isoform containing the epsilon-subunit shows shorter open times and high-amplitude
channel currents. Substitution of the epsilon-subunit for the γ-subunit gives
rise to the fast-gated, high-conductance channel type.
importance of acetylcholinesterase in normal and abnormal neuromuscular function.
