266
Chapter 9
opening many more ion channels. For this reason, one EPP is
normally more than suffi cient to depolarize the muscle plasma
membrane adjacent to the end-plate membrane to its thresh-
old potential, initiating an action potential. This action poten-
tial is then propagated over the surface of the muscle fi ber by
the same mechanism described in Chapter 6 for the propaga-
tion of action potentials along unmyelinated axon membranes.
Most neuromuscular junctions are located near the middle of
a muscle fi ber, and newly generated muscle action potentials
propagate from this region in both directions toward the ends
of the fi ber and throughout the T-tubule network.
To repeat, every action potential in a motor neuron
normally produces an action potential in each muscle fi ber in
its motor unit. This is quite different from synaptic junctions
between neurons, where multiple EPSPs must occur in order
for threshold to be reached and an action potential elicited in
the postsynaptic membrane.
There is a second difference between interneuronal syn-
apses and neuromuscular junctions. As we saw in Chapter 6,
IPSPs (inhibitory postsynaptic potentials) are produced at
some synaptic junctions. They hyperpolarize or stabilize the
postsynaptic membrane and decrease the probability of its fi r-
ing an action potential. In contrast, inhibitory potentials do
not occur in human skeletal muscle;
all neuromuscular junc-
tions are excitatory.
In addition to receptors for ACh, the synaptic junction
contains the enzyme
acetylcholinesterase,
which breaks
down ACh, just as it does at ACh-mediated synapses in the
nervous system. Choline is then transported back into the axon
terminals, where it is reused in the synthesis of new ACh. ACh
bound to receptors is in equilibrium with free ACh in the cleft
between the nerve and muscle membranes. As the concentra-
tion of free ACh falls because of its breakdown by acetylcholin-
esterase, less ACh is available to bind to the receptors. When
the receptors no longer contain bound ACh, the ion channels
in the end plate close. The depolarized end plate returns to its
resting potential and can respond to the subsequent arrival of
ACh released by another neuron action potential.
Table 9–2
summarizes the sequence of events that lead
from an action potential in a motor neuron to the contraction
and relaxation of a skeletal muscle fi ber.
Disruption of Neuromuscular Signaling
There are many ways by which disease or drugs can modify
events at the neuromuscular junction. For example, the deadly
South American arrowhead poison
curare
binds strongly to
nicotinic ACh receptors, but it does not open their ion chan-
nels and acetylcholinesterase does not destroy it. When a recep-
tor is occupied by curare, ACh cannot bind to the receptor.
Therefore, although the motor nerves still conduct normal
action potentials and release ACh, there is no resulting EPP
in the motor end plate and no contraction. Because the skel-
etal muscles responsible for breathing, like all skeletal muscles,
depend upon neuromuscular
transmiss
ion
to
initiate
the
ir
contraction, curare poisoning can cause death by asphyxia-
tion. Drugs similar to curare (
succinylcholine
is one example)
are used in small amounts to prevent muscular contractions
during certain types of surgical procedures when it is neces-
sary to immobilize the surgical fi eld. The use of such paralytic
agents also reduces the required dose of general anesthetic,
allowing patients to recover faster and with fewer complica-
tions. Patients are artifi
cially ventilated to maintain respiration
until the drug has been removed from the system.
Neuromuscular transmission can also be blocked by inhib-
iting acetylcholinesterase. Some organophosphates, which are
the main ingredients in certain pesticides and “nerve gases”
(the latter developed for chemical warfare), inhibit this enzyme.
In the presence of such agents, ACh is released normally upon
the arrival of an action potential at the axon terminal and binds
to the end-plate receptors. The ACh is not destroyed, how-
ever, because the acetylcholinesterase is inhibited. The ion
channels in the end plate therefore remain open, producing
a maintained depolarization of the end plate and the muscle
plasma membrane adjacent to the end plate. A skeletal muscle
membrane maintained in a depolarized state cannot generate
action potentials because the voltage-gated sodium channels
in the membrane become inactivated, which requires repo-
larization to reverse. After prolonged exposure to ACh, the
receptors of the motor end plate become insensitive to it, pre-
venting any further depolarization. Thus, the muscle does
not contract in response to subsequent nerve stimulation, and
the result is skeletal muscle paralysis and death from asphyx-
iation. Note that nerve gases also cause ACh to build up at
muscarinic synapses, for example, where parasympathetic neu-
rons inhibit cardiac pacemaker cells (Chapter 12). Thus, the
antidote for nerve gas exposure must include the muscarinic
receptor antagonist
atropine
.
A third group of substances, including the toxin pro-
duced by the bacterium
Clostridium botulinum,
blocks the
release of acetylcholine from nerve terminals. Botulinum
toxin is an enzyme that breaks down proteins of the SNARE
complex that are required for the binding and fusion of ACh
vesicles with the plasma membrane of the axon terminal
(review Figure 6–27). This toxin, which produces the food
poisoning called
botulism,
is one of the most potent poisons
known because of the very small amount necessary to produce
an effect. Application of botulinum toxin is increasingly being
used for clinical and cosmetic procedures, including the inhi-
bition of overactive extraocular muscles, prevention of exces-
sive sweat gland activity, treatment of migraine headaches, and
reduction of aging-related skin wrinkles.
Mechanics of Single-Fiber
Contraction
The force exerted on an object by a contracting muscle is known
as muscle
tension,
and the force exerted on the muscle by an
object (usually its weight) is the
load.
Muscle tension and load
are opposing forces. Whether a fi ber shortens depends on the
relative magnitudes of the tension and the load. For muscle
fi bers to shorten, and thereby move a load, muscle tension must
be greater than the opposing load.
When a muscle develops tension but does not shorten (or
lengthen), the contraction is said to be
isometric
(constant
length). Such contractions occur when the muscle supports a
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