Basic Mechanism of Synaptic Firing at
the Neuromuscular Junction
Elizabeth Gardner
What is a Neuromuscular Junction?
A neuromuscular junction (NMJ) is a synaptic site at which a motor neuron
innervates, or excites, a muscle fiber to cause the muscle’s contraction. Each
muscle fiber contains only one NMJ, so the overall strength of a muscle
contraction corresponds to cumulative synaptic firing of several neuromuscular
junctions at several muscle fibers. These synaptic sites serve as the nexus
between the nervous system and the muscular system.
The NMJ is implicated in several diseases. Myasthenia Gravis is a
neurodegenerative autoimmune disease in which the host’s antibodies target
essential neurotransmitter receptors in the NMJ. Dysfunction of the NMJ also has
a role in botulism. Upon exposure to the botulinum toxin released by the
bacterium Clostridium botulinum, a victim is rendered paralyzed due to NMJ
synaptic blockage. Consequently, the NMJ is the target of the cosmetic drug
Botox, which also contains botulinum toxin.
The NMJ is important to study not only for clinical purposes, however, but also
because it is one of the simplest neuronal networks. The synaptic mechanism at
the neuromuscular junction provides a prototypical example of how neurons
interact with one another to propagate a signal and execute a function.
How Does a Neuron Fire? An Introduction to
Action Potentials
Nerve cells, or neurons, are cells specialized for rapid, long distance intercellular
communication. Neurons achieve this quick signaling by utilizing the properties
of electricity.
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Neurons naturally host an electrical imbalance with their environment—that is,
the inside of the cell is negatively charged while the outside is positively
charged. The cell’s normal voltage is called its resting potential, which is
typically held at -70 mV. When intracellular ion concentrations fluctuate, the
cell’s voltage changes and functional consequences can ensue.
In contrast to the cell’s resting potential, its action potential indicates the voltage
threshold at which a cell will fire—i.e. the potential at which voltage sensitive
mechanisms within the neuron will activate and the neuron will send the signal
to another cognate neuron and/or execute a particular function (like contract a
muscle). Action potentials are normally held at a voltage that is less negative
than the resting potential. For example, a neuron’s resting potential may be -70
mV, but its action potential is at -40 mV. Thus, depolarizing currents of
sufficient magnitude can fire action potentials (in contrast to hyperpolarizing
currents, which cause a neuron’s membrane to become more negatively charged,
and make a neuron less likely to fire an action potential).
If a neuron’s function is to activate another cell, the firing of the action potential
will result in the release of neurotransmitter (a type of signaling chemical) from
the presynaptic neuron to the postsynaptic cell. The neurotransmitter will bind
to ligand-gated ion channels in the postsynaptic cell, which will cause the
channel to open and the ion concentration in the postsynaptic cell to fluctuate.
If the action potential is achieved, the postsynaptic cell will fire.
Structure of the NMJ synapse
In order to analyze the mechanism of action at the NMJ, it is essential to first
describe the three major structural elements at the synapse. Refer to Figure 1.
Synaptic Cleft
The synaptic cleft is the space between the neuron and the cell with which it
interacts. Neurotransmitters, which are neuron-specific chemicals that serve as
signaling molecules, are released into this area when the neuron fires.
Axon Terminal
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The axon terminal is the site within the presynaptic motor neuron at which the
neurotransmitters are stored and ultimately released upon activation. The
presynaptic axon terminals also contain neurotransmitter reuptake pumps that
collect unused neurotransmitter from synaptic cleft.
Dendritic Spine
The dendritic spine is the location on the postsynaptic muscle fiber cell at which
the neurotransmitter binds to its receptor and propagates the electrical signal
throughout the muscle. The dendritic spine is home to the post-synaptic
density, which is a cluster of proteins that are specialized to maintain proper
structure and function of the junction.
Figure 1. Synapse at the NMJ.
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Mechanism of Synaptic Action at the NMJ
The mechanism of synaptic action at the NMJ is the series of molecular and
electrophysiological steps required to contract a muscle cell as facilitated by the
intersection of a motor neuron and a muscle fiber cell. Muscle contraction at the
synaptic level requires six basic steps: presynaptic cell activation,
neurotransmitter release, receptor binding, muscle contraction, neurotransmitter
recycling, and receptor reactivation.
1. Presynaptic Cell Activation
First, the presynaptic motor cell must reach its action potential. In this case, a
signal from the brain is the original source of the traveling action potential.
2. Neurotransmitter Release
Next, the action potential triggers the opening of voltage-gated calcium
channels, which cause a rapid influx of positively charged calcium ions. Vesicles
containing previously synthesized neurotransmitters are in a “cocked” position at
the plasma membrane via SNARE complexes. These SNARE complexes, which
are calcium-dependent proteins responsible for rapid vesicle fusion, become
activated upon calcium binding and the synaptic vesicles are released into the
synaptic space.
Figure 2. Ligand-gated sodium channel. In the NMJ, the ligand,
or “messenger”, would be acetylcholine neurotransmitter. Sodium
would move into the open ion channel and cause a depolarizing
voltage change within the cell (cytosolic side).
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3. Receptor Binding
The neurotransmitters, which are acetylcholine (Ach) molecules at the NMJ,
diffuse through the synaptic cleft and specifically bind acetylcholine receptors.
These receptors are ligand-gated ion channels; in particular, they are
acetylcholine-gated sodium channels (see Figure 2 1 ). Two Ach molecules are
required to activate the receptor. Upon binding, the channel (receptor) then
undergoes a conformational change and opens to allow an influx of positively
charged sodium ions.
4. Muscle Contraction
Sufficient receptor sodium influx causes the
muscle fiber cell to depolarize and the
action potential is reached. The action
potential travels throughout the membrane
of the muscle fiber (the sarcolemma), and
voltage-gated ion channels release calcium
to
activate
calcium-dependent
motor
proteins that contract myofibrils in the
muscle cell (see Figure 2).
5. Neurotransmitter Recycling
Acetylcholinesterase enzymes on the
surface of the postsynaptic muscle cell
membrane catalyze the breakdown of the
acetylcholine neurotransmitter in order to
keep the signal brief.
Specifically,
acetylcholinesterase
hydrolyzes
the
neurotransmitter to produce choline. The
choline produced from the reaction is then
1
Figure 3. NMJ at the cellular
level. (1) and (3) indicate the
presynaptic motor neuron and
postsynaptic muscle fiber,
respectively. (2) represents the
axon terminal and location of the
synapse. (4) illustrates a
myofibril, which contracts upon
calcium release.
Membrane Receptors. Gentaur, n.d. Web. 20 Mar. 2015.
<http://membranereceptors.com/transduction-process/ion-channel-linked-receptors/>.
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pumped into a choline transporter on the surface of the presynaptic motor
neuron membrane and further sequestered into a synaptic vesicle by a vesicular
choline transporter. Within the vesicle, the choline is recycled back into Ach by
the enzyme choline acetyltransferase and the neurotransmitters are thusly
replenished in the motor neuron.
6. Receptor Reactivation
When Ach initially binds its receptor, the ion channel opens to allow for the
voltage changes that trigger the action potential. However, soon after the
channels have been opened, the receptors adopt an inactive conformation in
which the Ach is bound, but the channel is closed. Given sufficient time, the
closed channel allows for voltage-rectifying ion pumps to restore the cell to
resting potential. When the membrane repolarizes to resting potential, the old
Ach is released from the receptor and the receptor regains sensitivity for its
neurotransmitter so it can respond to a new signal.
The NMJ synaptic mechanism describes the steps required to contract a muscle
from a neuronal perspective. The process requires presynaptic cell activation,
neurotransmitter release, receptor binding, muscle contraction, neurotransmitter
recycling, and receptor reactivation. Because the NMJ is the canonical synapse,
these steps also describe broadly understood mechanisms across many neuronal
junction types. Comprehension of the mechanisms underlying synaptic function
at the NMJ is an essential first step to understanding the vast complexities that
the field of neuroscience offers.