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    • Abstract: Update inAnaesthesiaOriginally published in Update in Anaesthesia, edition 2 (1992) and 12 (2000)The Physiology of the Neuromuscular JunctionClare Ackroyd, Carl Gwinnutt**Correspondence Email: [email protected]

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Update in
Anaesthesia
Originally published in Update in Anaesthesia, edition 2 (1992) and 12 (2000)
The Physiology of the Neuromuscular Junction
Clare Ackroyd, Carl Gwinnutt*
*Correspondence Email: [email protected]
ThE MoToR NEURoNE of the neurotransmitter acetylcholine occurs with Summary
Motor neurones are the nerves that control skeletal consequent binding to the receptors on the motor
The neuromuscular
muscle activity. They originate in the ventral horn endplate.
junction is made up of a
of the spinal cord and travel up to a metre to the motor neurone and a motor
muscles they supply. The cell body of a neurone is at ThE MoToR ENDPlATE
endplate with a synaptic
its proximal end and impulses travel from here down The motor endplate is a highly specialised region of
cleft or junctional gap
the axon. Axons are 10-20 micrometers in diameter the sarcolemma of a muscle fibre. It is oval in shape dividing them. It is critical in
and surrounded by a myelin sheath, produced by and covers an area of about 3000mcm2. Its surface is the production of skeletal
Schwann cells. This acts as insulation to speed up deeply folded with multiple crests and secondary clefts. muscle contraction.
nerve conduction. The myelin sheath is interrupted The nicotinic acetylcholine receptors are located on
An understanding of the
by nodes of Ranvier between which the action the crests of the folds in great numbers (1-10 million) structure and physiology
potential jumps, allowing rapid conduction of the and concentration (10,000-20,000 per mcm2) to of the neuromuscular
nerve impulse (saltatory conduction). ensure the success of this effector system. The clefts of junction is essential for the
the motor endplate contain acetylcholinesterase. safe use of muscle relaxant
Each motor neurone connects to several skeletal drugs used in anaesthesia
muscle fibres to form a motor unit. The number of The area of muscle around the motor endplate is called
and intensive care, and for
muscle fibres within the motor unit varies enormously, the peri-junctional zone. Here the potential developed
understanding pathological
from a few, for fine motor control (e.g. the muscles at the endplate is converted to an action potential that states affecting the
of the eye), to several thousand for coarse actions propagates through the muscle to initiate contraction. neuromuscular
(e.g. the thigh muscles). There is however only one The peri-junctional zone has an enhanced ability to junction.
neuromuscular junction on each skeletal muscle fibre, produce a wave of depolarisation through the muscle
with all others being eliminated during development. from that produced by the post-synaptic receptors.
As the motor neurone enters a muscle, the axon ACETylCholiNE SyNThESiS, SToRAgE AND
divides into telodendria, the ends of which, the RElEASE
terminal buttons, synapse with the motor endplate. Acetylcholine is synthesised from choline and acetyl-
The two are separated by approximately 20nm, the coenzyme A (acetyl-coA) in the terminal axoplasm
junctional gap or synaptic cleft. It is here that release of motor neurones, catalysed by the enzyme choline
acetyltransferase. Acetyl-coA is
synthesised from pyruvate in
the mitochondria in the axon
terminals. Approximately 50%
of the choline is extracted from
extracellular fluid by a sodium Clare Ackroyd
dependant active transport Specialist Registrar
system, the other 50% is from Department of Anaesthesia
acetylcholine breakdown at Derriford Hospital
the neuromuscular junction. Crownhill
Overall, the majority of the Plymouth PL6 8DH
choline originates from the UK
diet with hepatic synthesis
only accounting for a small Carl Gwinnutt
proportion. Consultant
Department of Anaesthesia
Choline acetyltransferase is Hope Hospital
produced on the ribosomes Salford M6 8HD
Figure 1. The motor neurone in the cell body of the motor UK
Update in Anaesthesia | www.worldanaesthesia.org page 40
ACETylCholiNE RECEPToRS
The post-junctional membrane
receptors of the motor 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 protein comprised of five
polypeptide subunits that form a ring
structure around a central, funnel-
shaped pore (the ion channel). The
mature adult receptor has two identical
α (alpha) subunits, one β (beta), one
δ (delta) and one ε (epsilon) subunit.
In the fetus a γ (gamma) subunit
replaces the ε. These different proteins
are each coded by a different gene
and synthesised within the muscle
cells. The whole receptor spans the
muscle cell membrane projecting
predominantly extracellularly.
Figure 2. The neuromuscular junction Acetylcholine molecules bind to specific sites on the α subunits and
when both are occupied a conformational change occurs, opening
neurone from where it is transported distally by axoplasmic flow to the ion channel for just 1msec. The channel allows movement of all
the terminal button and can be found in high concentrations. The cations, however it is the movement of sodium that predominates in
activity of choline acetyltransferase is inhibited by acetylcholine and terms of both quantity and effect. This causes depolarisation, the cell
increased by nerve stimulation. becomes less negative compared with the extracellular surroundings.
When a threshold of –50mV is achieved (from a resting potential
Once synthesised the molecules of acetylcholine are stored in vesicles
of –80mV), voltage-gated sodium channels open, thereby increasing
within the terminal button, each vesicle containing approximately
the rate of depolarisation and resulting in an endplate potential
10,000 molecules of acetylcholine. These vesicles are loaded with
(EPP) of 50-100mV. This in turn triggers the muscle action potential
acetylcholine via a magnesium dependent active transport system
that results in muscle contraction. By this method the receptor acts
in exchange for a hydrogen ion. The vesicles then become part of
as a powerful amplifier and a switch (acetylcholine receptors are not
one of three pools or stores, each varying in their availability for
refractory).
release. About 1% are immediately releasable, about 80% are readily
releasable and the remainder form the stationary store. The exact In addition to the post-junctional receptors on the motor endplate,
proportions may vary depending on the level of demand or nerve acetylcholine receptors can also be found outside the neuromuscular
stimulation. junction and are called extra-junctional receptors, or on the pre-
terminal bulb and are called pre-junctional receptors. The extra-
The release of acetylcholine into the synaptic cleft may be spontaneous
junctional receptors can be present anywhere on the muscle
or in response to a nerve impulse. Spontaneous release of single
membrane usually in extremely small numbers, though they are
vesicles of acetylcholine occurs randomly and results in miniature
found in their greatest concentration around the endplate in the peri-
endplate potentials (MEPP) of 0.5-1mV, the function of which is
junctional zone. Denervation injuries and burns are associated with
unknown. With the arrival of a nerve impulse, large numbers of P-
large increases in the number of extra-junctional receptors on the
type calcium channels in the terminal membrane of the nerve open,
muscle membrane. The extra-junctional receptors have the structure
allowing calcium to enter the cell. The combination of depolarisation
of immature foetal receptors (ε subunit replaced by a γ subunit).
of the presynaptic terminal and influx of calcium triggers 100-300
This affects the physiology and pharmacology of the receptor with
vesicles to fuse with the presynaptic membrane at specific release
increased sensitivity to depolarising muscle relaxants and reduced
sites opposite the junctional folds and release acetylcholine into
sensitivity to non-depolarising muscle relaxants.
the synaptic cleft (exocytosis). This causes a brief depolarisation
in the muscle that triggers a muscle action potential (see below). Pre-junctional receptors on the terminal bulb have a positive feedback
The depleted vesicles are rapidly replaced with vesicles from the role. In very active neuromuscular junctions acetylcholine binds to
readily releasable store and the empty vesicles are recycled. At rest these receptors and causes an increase in transmitter production via
the free calcium concentration is kept below 10–6M (molar) by a a second messenger system. These receptors may also play a role
low membrane permeability to calcium, an active sodium/calcium in the ‘fade’ seen in non-depolarising muscle relaxant blockade by
exchange pump and mitochondrial sequestration. inhibiting replenishment of acetylcholine.
page 41 Update in Anaesthesia | www.anaesthesiologists.org
molecule has two distinct regions, an ionic site possessing a glutamate
residue and an esteratic site containing a serine residue. Hydrolysis
δ α
occurs with transfer of the acetyl group to the serine group resulting
in an acetylated molecule of the enzyme and free choline. The
ε β acetylated serine group then undergoes rapid, spontaneous hydrolysis
to form acetate and enzyme ready to repeat the process. The speed
α at which this occurs can be gauged by the fact that approximately
10,000 molecules of acetylcholine can be hydrolysed per second by
a single site.
Figure 3. Cross section of the acetylcholine receptor
This enzyme is secreted by the muscle cell but remains attached to
ACETylCholiNESTERASE it by thin collagen threads linking it to the basement membrane.
In order for the acetylcholine receptor to function effectively as a Acetylcholinesterase is found in the junctional gap and the clefts of
‘switch’ it is essential that acetylcholine is removed rapidly from the the post-synaptic folds and breaks down acetylcholine within 1ms of
junctional gap or synaptic cleft. This is achieved by hydrolysis of being released. Therefore the inward current through the acetylcholine
acetylcholine to choline and acetate in a reaction catalysed by the receptor is transient and followed by rapid repolarisation to the
enzyme acetylcholinesterase (AChE). The active site in the AchE resting state.
Update in Anaesthesia | www.worldanaesthesia.org page 42


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