June 16, 2025 • 21 mins
Let’s Get Updated is an audio learning series that brings to life the key topics from Update in Anaesthesia—one topic at a time. Each episode guides you through a full reading of a selected topic, making it easy to listen and read along. Whether you’re preparing for exams or brushing up on essential concepts, this podcast is built for anaesthesia learners in all settings, especially low-resource environments. This is an independent educational project not affiliated with the World Federation of Societies of Anaesthesiologists (WFSA). Content is drawn from publicly available issues of Update in Anaesthesia.
~~~~~~~~~~
This episode features a full reading of “The Physiology of the Neuromuscular Junction” from Update in Anaesthesia, Volume 24, Number 2. Read along with the original article or simply listen in for a clear, guided walkthrough. Let’s get updated.
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
(00:01):
Updating Anaesthesia Volume 24 #2 The Physiology of the
Neuromuscular junction by ClaireAykroyd and Carl Guinnot Summary
(00:24):
The neuromuscular junction is made-up of a Moto neuron, an
immortal endplate with a synaptic cleft or junctional gap
dividing them. It is critical in the production
of skeletal muscle contraction. An understanding of the
(00:46):
structure and Physiology of the neuromuscular junction is
essential for the safe use of muscle relaxant drugs used in
anaesthesia and intensive care, and for understanding
pathological states affecting the neuromuscular junction.
(01:10):
The motor neuron Motor neurons are the nerves that control
skeletal muscle activity. They originate in the ventral
horn of the spinal cord and travel up to a metre to the
(01:31):
muscles they supply. The cell body of a neuron is at
its proximal end and impulses travel from here down the Axon.
Axons are 10 to 20 micrometres in diameter and surrounded by a
(01:54):
myelin sheath produced by Schwann cells.
These acts as insulation to speed up nerve conduction.
The myelin sheet is interrupted by nodes of ravia between which
(02:16):
the action potential jumps, allowing rapid conduction of the
nerve impulse, that is, salutatory conduction.
Each motor neuron connects to several skeletal muscle fibres
(02:37):
to form a motor unit. The number of muscle fibres
within the motor unit varies enormously, from a few for fine
motor control, for example the muscles of the eye, to several
(02:59):
thousand for course actions, forexample the thigh muscles.
There is, however, only one neuromuscular junction on each
skeletal muscle fibre, with all others being eliminated during
development. As the motor neuron enters a
(03:24):
muscle, the Axon divides into thelodendria, the ends of which
the terminal bottle buttons synapse with the motor end
plate. The two are separated by
approximately 20 nanometers, thejunctional gap or synaptic
(03:51):
cleft. It is here that release of the
neurotransmitter acetylcholine occurs, with consequent binding
to the receptors on the Moto endplate.
The Moto Endplate The Moto endplate is a highly specialised
(04:19):
region of the sacroleum of a muscle fibre.
It is over in shape and covers an area of about 3000 micro
centimetre square. Sorry, 3000 let's take it again.
(04:45):
It is over in shape and covers an area of about 3000 micrometre
square. Its surface is deeply folded
with multiple crests and secondary clefts.
The nicotinic acetylcholine receptors are located on the
(05:10):
crests of the folds in great numbers, that is 1 to 10 million
and concentration that is 10,000to 2000 per micrometre square.
To ensure the success of this effector system, the clefts of
(05:33):
the Moto endplate contain acetylcollinesteries.
The area of muscle around the Moto endplate is called the
Perry junctional zone. Here the potential developed at
(05:53):
the endplate is converted to an action potential that propagates
through the muscle to initiate contraction.
The Perry junctional zone has anenhanced ability to produce a
wave of depolarization through the muscle form that produced by
(06:17):
the post synaptic receptors. Sorry.
The Perry junctional zone has anenhanced ability to produce a
wave of depolarization through the muscle from that produced by
the post synaptic receptors. Acetylcholine synthesis,
(06:41):
storage, and release. Acetylcholine is synthesised
from choline and acetyl coenzymeA in the terminal axoplasm of
motor neurons catalysed by the enzyme choline acetyl
(07:05):
transferase. Acetylchol A is synthesised from
pyruvate in the mitochondria in the Axon terminals.
Approximately 50% of the cholineis extracted from extracellular
(07:26):
fluid by a sodium dependent active transport system.
The other 50% is from acetylcholine breakdown at the
neuromuscular junction. Overall, the majority of the
choline originates from the diet, with hepatic synthesis
(07:49):
only accounting for a small proportion.
Next we get to Figure 1, the diagram of the motor neuron.
Kindly pause this recording to go through Figure 1.
(08:12):
Choline acetyl transferase is produced on the ribosomes in the
cell body of the motor neuron, from where it is transported
distally by axoplasmic flow to the terminal bottom and can be
found in high concentrations. The activity of choline acetyl
(08:39):
transferase is inhibited by acetylcholine and increased by
nerve stimulation. Next we get to Figure 2, showing
the diagram of the neuromuscularjunction.
Kindly pause this recording to go through Figure 2.
(09:06):
Once synthesised, the molecules of acetylcholine are stored in
vesicles within the terminal button, each vesicle containing
approximately 10,000 molecules of acetylcholine.
These vesicles are loaded with acetylcholine via a magnesium
(09:31):
dependent active transport system in exchange for a
hydrogen ion. The vesicles then become part of
one of three poles or stalls, each varying in their
availability for release. About 1% are immediately
(09:54):
releasable, about 80% are readily releasable, and the
remainder form the stationary store.
The exact proportions may vary depending on the level of demand
or nerve stimulation. The release of acetylcholine
(10:20):
into the synaptic cleft may be spontaneous or in response to a
nerve impulse. Spontaneous release of single
vesicles of acetylcholine occursrandomly and results in
miniature endplate potentials, that is, Mepp of 0.5 to 1
(10:46):
millivolts, the function of which is unknown.
With the arrival of nerve impulse, large numbers of P type
calcium channels in the terminalmembrane of the nerve open
allowing calcium to enter the cell.
(11:10):
The combination of depolarization of the pre
synaptic terminal and influx of calcium triggers 100 to 300
vesicles to fuse with the pre synaptic membrane at specific
release sites opposite the junctional folds and release
(11:34):
acetylcholine into the synaptic cleft that is exocytosis.
This causes a brief depolarization in the muscle
that triggers a muscle action potential.
(11:55):
The depleted vessels are rapidlyreplaced with vesicles from the
readily releasable store, and the empty vesicles are recycled
at rest. The free calcium concentration
is kept below 5:50 molar by a low membrane.
(12:19):
Permeability to calcium and active sodium.
Calcium exchange pump and mitochondrial sequestration.
Acetylcholine receptors. The post junctional membrane
(12:44):
receptors of the mol 2 endplate are nicotinic acetylcholine
receptors. There are on average 50 million
acetylcholine receptors on a normal endplate situated on the
crests of the junctional folds. Each nicotinic receptor is a
(13:12):
protein comprised of five polypeptide subunits that form a
ring structure around the central funnel shaped pore that
is the ion channel. The mature adult receptor has
two identical alpha subunits, 1 beta 1D and 1 epsilon subunit.
(13:46):
In the foetus, A gamma subunit replaces the epsilon.
These different proteins are each coded by different gene and
synthesised within the muscle cells.
(14:06):
The whole receptor spans the muscle cell membrane, projecting
predominantly extracellularly. Acetylcholine molecules bind to
specific sites on the alpha subunits, and when both are
(14:27):
occupied, A conformational change occurs, opening the ion
channel for just one millisecond.
The channel allows movement of all cations.
However, it is the movement of sodium that predominates in
(14:48):
terms of both quantity and effect.
This causes depolarization. The cell becomes less negative
compared with the extracellular surroundings when a threshold of
-50 millivolts is achieved, Thatis, from a resting potential of
(15:12):
-80 millivolts, voltage gated sodium channels open, thereby
increasing the rate of depolarization and resulting in
an end plate potential EPP of 50to 100 millivolts.
(15:36):
This in turn triggers the muscleaction potential that results in
muscle contraction. By this method, the receptor
acts as a powerful amplifier anda switch.
That is, acetylcholine receptorsare not refractory.
(16:01):
In addition to the post junctional receptors on the
motor N plate, acetylcholine receptors can also be found
outside the neuromuscular junction and are called extra
junctional receptors or on the pre terminal bulb and are called
(16:23):
pre junctional receptors. The extra junctional receptors
can be present anywhere on the muscle membrane, usually in
extremely small numbers, though they are found in their greatest
concentration around the end plate in the peri junctional
(16:46):
zone. Denervation injuries and burns
are associated with large increases in the number of extra
junctional receptors on the muscle membrane.
The extra junctional receptors have the structure of immature
(17:08):
foetal receptors, that is, epsilon subunits replaced by a
gamma subunit. This affects the Physiology and
pharmacology of the receptor with increased sensitivity to
depolarizing muscle relaxants and reduced sensitivity to non
(17:34):
depolarizing muscle relaxants. Prejunctional receptors on the
terminal bulb have a positive feedback role in very active
neuromuscular junctions. Acetylcholine binds to these
(17:56):
receptors and causes an increasein transmitter production via a
second messenger system. These receptors may also play a
role in the fade seen in non depolarizing muscle relaxant
blockade by inhibiting replenishment of acetylcholine.
(18:23):
Next we get to Figure 3 with a diagram of the cross section of
the acetylcholine receptor. Kindly pause this recording.
Take a few moments to just go through Figure 3.
Acetylcholinesterase. In order for the acetylcholine
(18:49):
receptor to function effectivelyas a switch, it is essential
that acetylcholine is removed rapidly from the junctional gap
or synaptic cleft. This is achieved by hydrolysis
of acetylcholine to choline, an acetate, in a reaction catalysed
(19:15):
by the enzyme acetylcholinesterase.
The active site in the acetylcholinesterase molecule
has two distinct regions, an ionic site possessing A
glutamate residue and an esteratic site containing A
(19:40):
serine residue. Hydrolysis occurs with transfer
of the acetyl group to the serine group, resulting in an
acetylated molecule of the enzyme and free choline.
(20:00):
The acetylated serine group thenundergoes rapid spontaneous
hydrolysis. To form acetate and enzyme ready
to repeat the process. The speed at which this occurs
can be gauged by the fact that approximately 10,000 molecules
(20:24):
of acetylcholine can be hydrolyzed per second by a
single site. This enzyme is secreted by the
muscle cell but remains attachedto it by thin collagen threads
linking it to the basement membrane.
(20:47):
Acetylcholine esteros is found in the junctional gap and the
clefts of the post. Synaptic folds and breaks down
acetylcholine within one mic millisecond of being released.
Therefore, the inward current through the acetylcholine
(21:08):
receptor is transient and followed by a rapid
repolarization to the resting state.
Updating Anaesthesia Volume 24 #2 The Physiology of the
Neuromuscular junction by ClaireAykroyd and Carl Guinnot Summary
(00:24):
The neuromuscular junction is made-up of a Moto neuron, an
immortal endplate with a synaptic cleft or junctional gap
dividing them. It is critical in the production
of skeletal muscle contraction. An understanding of the
(00:46):
structure and Physiology of the neuromuscular junction is
essential for the safe use of muscle relaxant drugs used in
anaesthesia and intensive care, and for understanding
pathological states affecting the neuromuscular junction.
(01:10):
The motor neuron Motor neurons are the nerves that control
skeletal muscle activity. They originate in the ventral
horn of the spinal cord and travel up to a metre to the
(01:31):
muscles they supply. The cell body of a neuron is at
its proximal end and impulses travel from here down the Axon.
Axons are 10 to 20 micrometres in diameter and surrounded by a
(01:54):
myelin sheath produced by Schwann cells.
These acts as insulation to speed up nerve conduction.
The myelin sheet is interrupted by nodes of ravia between which
(02:16):
the action potential jumps, allowing rapid conduction of the
nerve impulse, that is, salutatory conduction.
Each motor neuron connects to several skeletal muscle fibres
(02:37):
to form a motor unit. The number of muscle fibres
within the motor unit varies enormously, from a few for fine
motor control, for example the muscles of the eye, to several
(02:59):
thousand for course actions, forexample the thigh muscles.
There is, however, only one neuromuscular junction on each
skeletal muscle fibre, with all others being eliminated during
development. As the motor neuron enters a
(03:24):
muscle, the Axon divides into thelodendria, the ends of which
the terminal bottle buttons synapse with the motor end
plate. The two are separated by
approximately 20 nanometers, thejunctional gap or synaptic
(03:51):
cleft. It is here that release of the
neurotransmitter acetylcholine occurs, with consequent binding
to the receptors on the Moto endplate.
The Moto Endplate The Moto endplate is a highly specialised
(04:19):
region of the sacroleum of a muscle fibre.
It is over in shape and covers an area of about 3000 micro
centimetre square. Sorry, 3000 let's take it again.
(04:45):
It is over in shape and covers an area of about 3000 micrometre
square. Its surface is deeply folded
with multiple crests and secondary clefts.
The nicotinic acetylcholine receptors are located on the
(05:10):
crests of the folds in great numbers, that is 1 to 10 million
and concentration that is 10,000to 2000 per micrometre square.
To ensure the success of this effector system, the clefts of
(05:33):
the Moto endplate contain acetylcollinesteries.
The area of muscle around the Moto endplate is called the
Perry junctional zone. Here the potential developed at
(05:53):
the endplate is converted to an action potential that propagates
through the muscle to initiate contraction.
The Perry junctional zone has anenhanced ability to produce a
wave of depolarization through the muscle form that produced by
(06:17):
the post synaptic receptors. Sorry.
The Perry junctional zone has anenhanced ability to produce a
wave of depolarization through the muscle from that produced by
the post synaptic receptors. Acetylcholine synthesis,
(06:41):
storage, and release. Acetylcholine is synthesised
from choline and acetyl coenzymeA in the terminal axoplasm of
motor neurons catalysed by the enzyme choline acetyl
(07:05):
transferase. Acetylchol A is synthesised from
pyruvate in the mitochondria in the Axon terminals.
Approximately 50% of the cholineis extracted from extracellular
(07:26):
fluid by a sodium dependent active transport system.
The other 50% is from acetylcholine breakdown at the
neuromuscular junction. Overall, the majority of the
choline originates from the diet, with hepatic synthesis
(07:49):
only accounting for a small proportion.
Next we get to Figure 1, the diagram of the motor neuron.
Kindly pause this recording to go through Figure 1.
(08:12):
Choline acetyl transferase is produced on the ribosomes in the
cell body of the motor neuron, from where it is transported
distally by axoplasmic flow to the terminal bottom and can be
found in high concentrations. The activity of choline acetyl
(08:39):
transferase is inhibited by acetylcholine and increased by
nerve stimulation. Next we get to Figure 2, showing
the diagram of the neuromuscularjunction.
Kindly pause this recording to go through Figure 2.
(09:06):
Once synthesised, the molecules of acetylcholine are stored in
vesicles within the terminal button, each vesicle containing
approximately 10,000 molecules of acetylcholine.
These vesicles are loaded with acetylcholine via a magnesium
(09:31):
dependent active transport system in exchange for a
hydrogen ion. The vesicles then become part of
one of three poles or stalls, each varying in their
availability for release. About 1% are immediately
(09:54):
releasable, about 80% are readily releasable, and the
remainder form the stationary store.
The exact proportions may vary depending on the level of demand
or nerve stimulation. The release of acetylcholine
(10:20):
into the synaptic cleft may be spontaneous or in response to a
nerve impulse. Spontaneous release of single
vesicles of acetylcholine occursrandomly and results in
miniature endplate potentials, that is, Mepp of 0.5 to 1
(10:46):
millivolts, the function of which is unknown.
With the arrival of nerve impulse, large numbers of P type
calcium channels in the terminalmembrane of the nerve open
allowing calcium to enter the cell.
(11:10):
The combination of depolarization of the pre
synaptic terminal and influx of calcium triggers 100 to 300
vesicles to fuse with the pre synaptic membrane at specific
release sites opposite the junctional folds and release
(11:34):
acetylcholine into the synaptic cleft that is exocytosis.
This causes a brief depolarization in the muscle
that triggers a muscle action potential.
(11:55):
The depleted vessels are rapidlyreplaced with vesicles from the
readily releasable store, and the empty vesicles are recycled
at rest. The free calcium concentration
is kept below 5:50 molar by a low membrane.
(12:19):
Permeability to calcium and active sodium.
Calcium exchange pump and mitochondrial sequestration.
Acetylcholine receptors. The post junctional membrane
(12:44):
receptors of the mol 2 endplate are nicotinic acetylcholine
receptors. There are on average 50 million
acetylcholine receptors on a normal endplate situated on the
crests of the junctional folds. Each nicotinic receptor is a
(13:12):
protein comprised of five polypeptide subunits that form a
ring structure around the central funnel shaped pore that
is the ion channel. The mature adult receptor has
two identical alpha subunits, 1 beta 1D and 1 epsilon subunit.
(13:46):
In the foetus, A gamma subunit replaces the epsilon.
These different proteins are each coded by different gene and
synthesised within the muscle cells.
(14:06):
The whole receptor spans the muscle cell membrane, projecting
predominantly extracellularly. Acetylcholine molecules bind to
specific sites on the alpha subunits, and when both are
(14:27):
occupied, A conformational change occurs, opening the ion
channel for just one millisecond.
The channel allows movement of all cations.
However, it is the movement of sodium that predominates in
(14:48):
terms of both quantity and effect.
This causes depolarization. The cell becomes less negative
compared with the extracellular surroundings when a threshold of
-50 millivolts is achieved, Thatis, from a resting potential of
(15:12):
-80 millivolts, voltage gated sodium channels open, thereby
increasing the rate of depolarization and resulting in
an end plate potential EPP of 50to 100 millivolts.
(15:36):
This in turn triggers the muscleaction potential that results in
muscle contraction. By this method, the receptor
acts as a powerful amplifier anda switch.
That is, acetylcholine receptorsare not refractory.
(16:01):
In addition to the post junctional receptors on the
motor N plate, acetylcholine receptors can also be found
outside the neuromuscular junction and are called extra
junctional receptors or on the pre terminal bulb and are called
(16:23):
pre junctional receptors. The extra junctional receptors
can be present anywhere on the muscle membrane, usually in
extremely small numbers, though they are found in their greatest
concentration around the end plate in the peri junctional
(16:46):
zone. Denervation injuries and burns
are associated with large increases in the number of extra
junctional receptors on the muscle membrane.
The extra junctional receptors have the structure of immature
(17:08):
foetal receptors, that is, epsilon subunits replaced by a
gamma subunit. This affects the Physiology and
pharmacology of the receptor with increased sensitivity to
depolarizing muscle relaxants and reduced sensitivity to non
(17:34):
depolarizing muscle relaxants. Prejunctional receptors on the
terminal bulb have a positive feedback role in very active
neuromuscular junctions. Acetylcholine binds to these
(17:56):
receptors and causes an increasein transmitter production via a
second messenger system. These receptors may also play a
role in the fade seen in non depolarizing muscle relaxant
blockade by inhibiting replenishment of acetylcholine.
(18:23):
Next we get to Figure 3 with a diagram of the cross section of
the acetylcholine receptor. Kindly pause this recording.
Take a few moments to just go through Figure 3.
Acetylcholinesterase. In order for the acetylcholine
(18:49):
receptor to function effectivelyas a switch, it is essential
that acetylcholine is removed rapidly from the junctional gap
or synaptic cleft. This is achieved by hydrolysis
of acetylcholine to choline, an acetate, in a reaction catalysed
(19:15):
by the enzyme acetylcholinesterase.
The active site in the acetylcholinesterase molecule
has two distinct regions, an ionic site possessing A
glutamate residue and an esteratic site containing A
(19:40):
serine residue. Hydrolysis occurs with transfer
of the acetyl group to the serine group, resulting in an
acetylated molecule of the enzyme and free choline.
(20:00):
The acetylated serine group thenundergoes rapid spontaneous
hydrolysis. To form acetate and enzyme ready
to repeat the process. The speed at which this occurs
can be gauged by the fact that approximately 10,000 molecules
(20:24):
of acetylcholine can be hydrolyzed per second by a
single site. This enzyme is secreted by the
muscle cell but remains attachedto it by thin collagen threads
linking it to the basement membrane.
(20:47):
Acetylcholine esteros is found in the junctional gap and the
clefts of the post. Synaptic folds and breaks down
acetylcholine within one mic millisecond of being released.
Therefore, the inward current through the acetylcholine
(21:08):
receptor is transient and followed by a rapid
repolarization to the resting state.
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