Neuromuscular junction

drg.Nursiah.Nasution Mkes
 Neuromuscular junction
A neuromuscular junction (NMJ) is the synapse
or junction of the axon terminal of a motoneuron
with the motor end plate, the highly-excitable
region of muscle fiber plasma membrane
responsible for initiation of action potentials
across the muscle's surface, ultimately causing
the muscle to contract.
In vertebrates, the signal passes through the
neuromuscular junction via the neurotransmitter
acetylcholine.
• Chemical synapses are specialized
junctions through which the cells of the
nervous system signal to each other and
to non-neuronal cells such as those in
muscles or glands.
• Chemical synapses allow the neurons of
the central nervous system to form
interconnected neural circuits.
• They are thus crucial to the biological
computations that underlie perception and
thought.
• They provide the means through which the
nervous system connects to and controls
the other systems of the body.
• A chemical synapse between a motor
neuron and a muscle cell is called a
neuromuscular junction; this type of
synapse is well-understood.
 \
• Young children have about 1016 synapses (10
quadrillion). This number declines with age,
stabilizing by adulthood. Estimates for adults
vary from 1015 to 5 × 1015 (1-5 quadrillion)
synapses.
• Chemical synapses are not the only type of
biological synapse: electrical and immunological
synapses exist as well. Without a qualifier,
however, "synapse" commonly refers to a
chemical synapse.
• The signal across a synapse may be regarded
as neurocrine, analogous to the types of
signaling of the endocrine system (endocrine,
paracrine and autocrine).
• The axon is a finer, cable-like projection which
can extend tens, hundreds, or even tens of
thousands of times the diameter of the soma in
length.
• The axon carries nerve signals away from the
soma (and also carry some types of information
back to it).
• Many neurons have only one axon, but this axon
may - and usually will - undergo extensive
branching, enabling communication with many
target cells.
• The part of the axon where it emerges from the
soma is called the axon hillock.
• Besides being an anatomical structure, the axon
hillock is also the part of the neuron that has the
greatest density of voltage-dependent sodium
channels.
• This makes it the most easily-excited part of the
neuron and the spike initiation zone for the axon:
in neurological terms it has the most negative
hyperpolarized action potential threshold.
• While the axon and axon hillock are generally
involved in information outflow, this region can
also receive input from other neurons.
• The axon terminal contains synapses,
specialized structures where
neurotransmitter chemicals are released in
order to communicate with target neurons.
• Although the canonical view of the neuron
attributes dedicated functions to its various
anatomical components, dendrites and
axons often act in ways contrary to their
so-called main function.
• Axons and dendrites in the central nervous
system are typically only about one
micrometer thick, while some in the
peripheral nervous system are much
thicker.
• The soma is usually about 10–25
micrometers in diameter and often is not
much larger than the cell nucleus it
contains.
• The longest axon of a human motoneuron
can be over a meter long, reaching from
the base of the spine to the toes.
• Sensory neurons have axons that run from
the toes to the dorsal columns, over 1.5
meters in adults.
• Giraffes have single axons several meters
in length running along the entire length of
their necks.
• Much of what is known about axonal
function comes from studying the squid
giant axon, an ideal experimental
preparation because of its relatively
immense size (0.5–1 millimeters thick,
several centimeters long).
• Function
• The interface between a motoneuron and
muscle fiber is a specialized synapse called the
neuromuscular junction.
• Upon adequate stimulation, the motoneuron
releases a flood of neurotransmitters that bind to
postsynaptic receptors and triggers a response
in the muscle fiber.
• In invertebrates, depending on the
neurotransmitter released and the type of
receptor it binds, the response in the muscle
fiber could be either excitatory or inhibitory.
• For vertebrates, however, the response of a
muscle fiber to a neurotransmitter can only be
excitatory, in other words, contractile.
• Muscle relaxation and inhibition of muscle
contraction in verterbrates is obtained only by
inhibition of the motorneuron itself.
• Although muscle innervation may eventually
play a role in the maturation of motor activity.
• This is why muscle relaxants work by acting on
the motoneurons that innervate muscles (by
decreasing their electrophysiological activity) or
on cholinergic neuromuscular junctions, rather
than on the muscles themselves.
 Somatic motoneurons
• Somatic motoneurons are further subdivided into
two types: alpha efferent neurons and gamma
efferent neurons. (Both types are called efferent
to indicate the flow of information from the
central nervous system (CNS) to the periphery.)
• Alpha motoneurons innervate extrafusal muscle
fibers (typically referred to simply as muscle
fibers) located throughout the muscle.
• Their cell bodies are in the ventral horn of the
spinal cord and they are sometimes called
ventral horn cells.
• Gamma motoneurons innervate intrafusal
muscle fibers found within the muscle spindle.
• In addition to voluntary skeletal muscle
contraction, alpha motoneurons also contribute
to muscle tone, the continuous force generated
by noncontracting muscle to oppose stretching.
• When a muscle is stretched, sensory neurons
within the muscle spindle detect the degree of
stretch and send a signal to the CNS.
• The CNS activates alpha motoneurons in the
spinal cord, which cause extrafusal muscle
fibers to contract and thereby resist further
stretching. This process is also called the stretch
reflex.
• Gamma motoneurons regulate the
sensitivity of the spindle to muscle
stretching.

• With activation of gamma neurons,

intrafusal muscle fibers contract so that
only a small stretch is required to activate
spindle sensory neurons and the stretch
reflex.
 Motor units
• A single motoneuron may synapse with
one or more muscle fibers. The
motoneuron and all of the muscle fibers to
which it connects is a motor unit.
• Phases :The sequence of events that
underlie the action potential have been
outlined below:
• Resting potential : At rest in many
neurons, potassium channels (both Kir
and K2P) are open while sodium channels
are closed.
• Though no net current flows, the resting
potential is pulled toward the K+ reversal
potential as K+ is the primary permeant
ion.
• Other tissue types, such as skeletal
muscle, can also have a large resting Cl-
conductance, increasing the resting
potential to more positive values.
Stimulation
• A local membrane depolarization
caused by an excitatory stimulus
causes some voltage-gated sodium
channels in the axon hillock
membrane to open, causing net
inward movement of sodium ions
through the channels along their
electrochemical gradient.
• This movement of sodium ions across
the membrane is an example of
facilitated diffusion[1].
• Because they are positively charged, the
inward moving sodium ions make the
potential difference across the membrane
less negative inside.

• This initial inward movement of sodium

ions is favored by both the negative-inside
membrane potential and the concentration
gradient of sodium ions across the
membrane (less sodium inside).
• The movement of individual
sodium ions involves many
random molecular collisions and
at any particular moment a
sodium ion might be moving
outward, but the net movement of
sodium is inward, as determined
by the electrochemical gradient.
 Depolarization ("Rising phase")
• As sodium ions enter and the membrane
potential becomes less negative, more
sodium channels open, causing an even
greater influx of sodium ions.
• This is an example of positive feedback.
As more sodium channels open, the
sodium current dominates over the
potassium leak current and the membrane
potential becomes positive inside.
• Recent experiments on cortical neurons
suggest that sodium channels open
cooperatively,[2] allowing for a much faster
uptake than is possible for Hodgkin-
Huxley–type dynamics.
 Peak
– See also: Goldman-Hodgkin-Katz
voltage equation
• By the time the membrane potential has
reached a peak value of around +50 mV,
time-dependent inactivation gates on the
sodium channels have already started to
close, reducing and finally preventing
further influx of sodium ions.
• While this occurs, the voltage-sensitive
activation gates on the voltage-gated
potassium channels begin to open.
• It is important to appreciate that very few
ions actually cross the membrane at any
stage in the action potential.
• There is no 'flood' of sodium into the cell;
the gross intracellular and extracellular
concentrations of sodium and potassium
change so little during the action potential
as to be negligible.
• Instead, the change in membrane polarity
occurs due to the Permeability for Sodium,
PNa, increasing greatly via the positive
feedback system described (depolarization
causes voltage-gated Sodium channels to
open, so membrane becomes more
depolarized etc).
• Increasing PNa relative to Potassium
Permeability (PK)affects voltage because
it lifts the membrane potential towards that
of the equilibrium potential for Sodium
(ENa), which is approximately +55mV.
• This can be measured quantitively using
the Goldman equation,
• Concentrations of Na and K in and out of
the cell do not change much, but PNa and
PK values do change markedly, and it is
this that changes the value for V.
 Repolarization ("Falling phase")
• As voltage-gated potassium channels
open, there is a large outward movement
of potassium ions driven by the potassium
concentration gradient and initially favored
by the positive-inside electrical gradient.
As potassium ions diffuse out, this
movement of positive charge causes a
reversal of the membrane potential to
negative-inside and repolarization of the
neuron back towards the large negative-
inside resting potential.
• Again, it is not the movement of potassium
ions that changes membrane voltage. It is
the value for PK rising above that for PNa,
dragging membrane voltage back towards
the equilibrium constant for Potassium
(around -70mV) (see Goldman Constant
Field Equation).
 Hyperpolarization ("Undershoot")
• Closing of voltage-gated potassium
channels is both voltage- and time-
dependent.
• As potassium exits the cell, the resulting
membrane repolarization initiates the
closing of voltage-gated potassium
channels.
• These channels do not close immediately in
response to a change in membrane potential;
rather, voltage-gated potassium channels (also
called delayed rectifier potassium channels)
have a delayed response, such that potassium
continues to flow out of the cell even after the
membrane has fully repolarized.

• Thus the membrane potential dips below the

normal resting membrane potential of the cell for
a brief moment; this dip of hyperpolarization is
known as the undershoot.
 Refractory Period
• During the next, ~ 1-3 ms, action potential
initiation becomes difficult. This is the
'Refractory Period', consisting of an
absolute and relative phase.
• In the absolute refractory period, the Na+
Channels cannot be opened by a stimulus;
they have entered an inactivated state.
• This is time-dependent, and during this
phase no action potential, irrespective of
applied voltage, will be fired.
• In the relative refractory period
(immediately after the absolute phase),
action potentials can be initiated, but the
threshold is greater.
• There are two reasons for this: the cell
may still be slightly hyperpolarized due to
still higher than resting value for PK, so
more voltage is required to reach
threshold, and also the threshold itself is
higher than usual because some of the
Sodium channels will still be inactivated.
• (Note that the sodium channel therefore
has at least three states: closed, open and
inactivated - closed and not able to open).
• The refractory period is important because
it ensures unidirectional (one way)
propagation of the action potential.
• There is a common misconception that the
Na+/K+ pump restores the resting potential
during the action potential falling phase by
actively pumping Na+ out of, and K+ into the
neuron.
• This (along with the misconception that sodium
'floods' the cell to cause the action potential), is
not correct.
• The Na+/K+/ATPase (another name for the
pump) does ultimately maintain the resting
potential by maintaining the concentration
gradients for Na and K, but does so on a much
slower time scale; days as opposed to
milliseconds.
• During the falling phase of the action
potential, the resting potential is restored
exclusively by PK rising to once again be
far larger than PNa (i.e. membrane
permeability to potassium far exceeds its
permeability to sodium, thus bringing the
membrane potential back down towards
EK (the potassium equilibrium potential).
• The time-course of the role of the
Na+/K+/ATPase in maintaining resting
potentials can be demonstrated by the fact
that the poison Ouabain inactivates the
Na+/K+/ATPase, yet many thousands of
action potentials can still be fired without
significantly running down the
concentration gradients.
 Threshold and initiation
• A plot of current (ion flux) against voltage
(transmembrane potential) illustrates the action
potential threshold (red arrow) of an idealized
cell.
• Action potentials are triggered when an initial
depolarization reaches the threshold.
• This threshold potential varies, but generally is
about 15 millivolts more positive than the cell's
resting membrane potential, occurring when the
inward sodium current exceeds the outward
potassium current.
• The net influx of positive charges carried
by sodium ions depolarizes the membrane
potential, leading to the further opening of
voltage-gated sodium channels.
• These channels support greater inward
current causing further depolarization,
creating a positive-feedback cycle that
drives the membrane potential to a very
depolarized level.
• The action potential threshold can be
shifted by changing the balance between
sodium and potassium currents. For
example, if some of the sodium channels
are in an inactivated state, then a given
level of depolarization will open fewer
sodium channels and a greater
depolarization will be needed to trigger an
action potential. This is the basis for the
refractory period (see Refractory period).
• Action potentials are largely dictated by
the interplay between sodium and
potassium ions (although there are minor
contributions from other ions such as
calcium and chloride), and are often
modeled using hypothetical cells
containing only two transmembrane ion
channels (a voltage-gated sodium channel
and a non-voltage-gated potassium
channel).
• The origin of the action potential threshold may
be studied using I/V curves (right) that plot
currents through ion channels against the cell's
membrane potential. (Note that the illustrated I/V
is an "instantaneous" current voltage
relationship.
• It represents the peak current through channels
at a given voltage before any inactivation has
taken place (i.e. ~ 1 ms after stepping to that
voltage) for the Na current.
• The most positive voltages in this plot are only
attainable by the cell through artificial means -
i.e. voltages imposed by the voltage-clamp
apparatus).
 Neurotransmitters
• Neurotransmitters are chemicals that are used to relay,
amplify and modulate signals between a neuron and
another cell.
• According to the prevailing beliefs of the 1960s, a
chemical can be classified as a neurotransmitter if it
meets the following conditions:
• There are precursors and/or synthesis enzymes located
in the presynaptic side of the synapse;
• The chemical must be present in the presynaptic
element
• It is available in sufficient quantity in the presynaptic
neuron to affect the postsynaptic neuron;
• There must be postsynaptic receptors and the ability for
the chemical to bind to said receptors
• A biochemical mechanism for inactivation must be
present.
• The chemical compound acetylcholine (ACh) is
a neurotransmitter in both the peripheral
nervous system (PNS) and central nervous
system (CNS) in many organisms including
humans.
• ACh is one of many neurotransmitters in the
autonomic nervous system (ANS) and the only
neurotransmitter used in the somatic nervous
system.
• It is also the neurotransmitter in all autonomic
ganglia.
• Chemistry
• Acetylcholine is an ester of acetic acid and choline with
chemical formula CH3COOCH2CH2N+(CH3)3. This
structure is reflected in the systematic name, 2-acetoxy-
N,N,N-trimethylethanaminium.
• Function
• Acetylcholine has functions both in the peripheral
nervous system (PNS) and in the central nervous system
(CNS) as a neuromodulator.
• In the PNS, acetylcholine activates muscles, and is a
major neurotransmitter in the autonomic nervous system.
• In the CNS, acetylcholine and the associated neurons
form a neurotransmitter system, the cholinergic system,
which tends to cause excitatory actions.
 In PNS
• In the peripheral nervous system, acetylcholine activates muscles,
and is a major neurotransmitter in the autonomic nervous system.
• When acetylcholine binds to acetylcholine receptors on skeletal
muscle fibers, it opens ligand gated sodium channels in the cell
membrane. Sodium ions then enter the muscle cell, stimulating
muscle contraction. Acetylcholine, while inducing contraction of
skeletal muscles, instead induces decreased contraction in cardiac
muscle fibers. This distinction is attributed to differences in receptor
structure between skeletal and cardiac fibers.
• In the autonomic nervous system, acetylcholine is released in the
following sites:
• all pre- and post-ganglionic parasympathetic neurons
• all preganglionic sympathetic neurons
– preganglionic sympathetic fibers to suprarenal medulla, the modified
sympathetic ganglion; on stimulation by acetylcholine, the suprarenal
medulla releases adrenaline and noradrenaline
• some postganglionic sympathetic fibers
– sudomotor neurons to sweat glands.
• In the autonomic nervous system, acetylcholine
is released in the following sites:
• all pre- and post-ganglionic parasympathetic
neurons
• all preganglionic sympathetic neurons
– preganglionic sympathetic fibers to suprarenal
medulla, the modified sympathetic ganglion; on
stimulation by acetylcholine, the suprarenal medulla
releases adrenaline and noradrenaline
• some postganglionic sympathetic fibers
– sudomotor neurons to sweat glands.
In CNS
• In the central nervous system, ACh has a variety of effects as a
neuromodulator, e.g., for plasticity and excitability. Other effects are
arousal and reward.
Structure
• Acetylcholine and the associated neurons form a neurotransmitter
system, the cholinergic system.
• It originates mainly in pontomesencephalotegmental complex, basal
optic nucleus of Meynert and medial septal nucleus, and projects
axons to vast areas of the brain:
• The pontomesencephalotegmental complex acts mainly on M1
receptors in the brainstem .
• Basal optic nucleus of Meynert acts mainly on M1 receptors in the
neocortex.
• Medial septal nucleus acts mainly on M1 receptors in the
hippocampus and neocortex.
• Communication of information between neurons is
accomplished by movement of chemicals across a small
gap called the synapse.
• Chemicals, called neurotransmitters, are released from
one neuron at the presynaptic nerve terminal.
• Neurotransmitters then cross the synapse where they
may be accepted by the next neuron at a specialized site
called a receptor.
• The action that follows activation of a receptor site may
be either depolarization (an excitatory postsynaptic
potential) or hyperpolarization (an inhibitory postsynaptic
potential).
• A depolarization makes it MORE likely that an action
potential will fire; a hyperpolarization makes it LESS
likely that an action potential
Mechanism
• Depolarization is often caused by influx of cations, e.g.
Na+ through Na+ channels, or by influx of Ca2+ through
Ca2+ channels.
• On the other hand, outflux of K+ through K+ channels
inhibits depolarization.
• If a cell has a resting potential of -70mV and the
membrane potential changes to -50mV, then the cell has
been depolarized.
Depolarization block
• There are drugs, called , that inhibit depolarization, e.g.
by blocking the channels responsible for depolarization,
or by opening K+ channels. Examples include the
nicotinic agonists suxamethonium and
decamethonium[1].
• In biology, depolarization is a decrease in the
absolute value of a cell's membrane potential.
Thus, changes in membrane voltage in which
the membrane potential becomes less positive
or less negative are both depolarizations.
• In neurons and some other cells, a
depolarization large enough may result in an
action potential.
• Hyperpolarization is the opposite of
depolarization, and inhibits the rise of an action
potential.
• The rising and falling phases of such an action
potential are often imprecisely also called
depolarization and hyperpolarization,
respectively
• Electron micrograph showing a cross section through
the neuromuscular junction. T is the axon terminal, M is
the muscle fiber. The arrow shows junctional folds with
basal lamina. Postsynaptic densities are visible on the
tips between the folds. Scale is 0.3 µm. Source: NIMH
• When a motor neuron enters a muscle, it loses
its myelin sheath and splits into many terminal
branches.
• Motor neuron (efferent) axons originating in the
spinal cord enter muscle fibers, where they split
into many unmyelinated branches.
• These terminal fibers run along the myocytes to
end at the neuromuscular junction, which
occupies a depression in the sarcolemma.
• Each motor neuron can innervate from one to
over 2000 [1] muscle fibers, but each muscle
fiber receives inputs from only one motor
neuron.
• In the terminal bouton of the motor nerve,
structures known as presynaptic active zones
accumulate synaptic vesicles filled with the
neurotransmitter acetylcholine.
• On the muscle side of the junction, the muscle
fiber is folded into grooves called postjunctional
folds that mirror the presynaptic active zones,
the spaces between the folds contain
acetylcholine receptors.
• The muscle surface is covered by the synaptic
basal lamina. Postjunctional folds are
characteristic of skeletal muscle, particularly in
fast muscle fibers.
• Anatomy
• Global view of a neuromuscular junction:
1. Axon
2. Motor end-plate
3. Muscle fiber
4. Myofibril
• Upon the arrival of an action potential at
the axon terminal, voltage-dependent
calcium channels open and Ca2+ ions
flow from the extracellular fluid into the
motor neuron's cytosol.
• This influx of Ca2+ triggers excitation-
contraction coupling, a biochemical
cascade that causes neurotransmitter-
containing vesicles to fuse to the motor
neuron's cell membrane and release
acetylcholine into the synaptic cleft.
• Acetylcholine diffuses across the synaptic
cleft and binds to the nicotinic
acetylcholine receptors that dot the motor
end plate.
• The receptors are ligand-gated ion
channels, and when bound by
acetylcholine, they open, allowing sodium
and potassium ions to flow in and out of
the muscle's cytosol, respectively.
• Because of the differences in electrochemical
gradients across the plasma membrane, more
sodium moves in than potassium out, producing
a local depolarization of the motor end plate
known as an end-plate potential (EPP).
• This depolarization spreads across the surface
of the muscle fiber into transverse tubules,
eliciting the release of calcium from the
sarcoplasmic reticulum, thus initiating muscle
contraction.
• The action of acetylcholine is terminated when
the enzyme acetylcholinesterase degrades the
neurotransmitter and the unhydrolysed
neurotransmitter diffuses away.
Detailed view of a
neuromuscular junction:
1. Presynaptic terminal
2. Sarcolemma
3. Synaptic vesicle
4. Nicotinic acetylcholine
receptor
5. Mitochondrion
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• The body contains over 600 different skeletal

muscles and each consists of thousands of
muscle fibres ranging in length from a few
millimetres to several centimetres.
• The motor nerve fibres innervating them, which
arise in the spinal cord, can be more than 1 m in
length.
• However, the area of apposition between the
terminal tip of each nerve fibre and the
‘endplate’ of each muscle fibre is usually less
than 50 μm (1/20 mm) in diameter.
• This particular type of synapse is called
the neuromuscular junction (see figure). In
order to generate the complex and finely
controlled movements that we all take for
granted, there has to be a very efficient,
fail-safe, and one-way transmission
between the nerve and the muscle that
ensures that muscle contractions faithfully
follow commands from the central nervous
system.
• Such neuromuscular transmission
depends on the release from the motor
nerve terminal of the chemical
acetylcholine (ACh), and its binding to a
protein receiver on the surface of the
muscle, called the acetylcholine receptor
(AChR).
• When a nerve impulse reaches the motor nerve
terminal, specialized proteins forming ion-
channels in its cell membrane open transiently,
allowing a short-lived entry of calcium into the
terminal.
• Stored inside the nerve terminal, and attached to
special sites on the inside of the cell membrane,
are small round vesicles filled with ACh.
• The sudden inrush of calcium causes some of
the vesicle membranes to fuse with the nerve
terminal membrane, and to release their
contents into the synaptic cleft between the
nerve and the surface of the muscle fibre (see
figure (d) ).
• ACh diffuses rapidly across the
ultramicroscopic 50 nm gap and binds to
the AChRs that are very densely packed
on the tops of the synaptic folds on the
muscle fibre (see figure (c), (d) ).
• When two ACh molecules bind to each
AChR, its central pore (channel) opens,
allowing small positively charged ions,
mainly sodium, to enter the muscle,
resulting in a local reduction in the
potential across the membrane
(depolarization).
• The release of many ACh-containing
vehicles by a nerve impulse leads to a
large depolarization called the endplate
potential, which in turn opens the voltage-
sensitive sodium channels situated at the
base of each synaptic fold (see figure (d) ).

• These are responsible for starting an ‘all or

nothing’ action potential that is propagated
along the muscle fibre in each direction
and initiates muscle contraction.
• After about a millisecond, the AChR pore closes
and ACh unbinds and is broken down by an
enzyme, ACh esterase (AChE), that sits in the
synaptic cleft (see figure (d) ).
• Choline is then taken back into the nerve
terminal by special transporters, and used to
make more ACh; this is stored in newly-formed
synaptic vesicles, themselves made up of
recycled nerve terminal membrane.
• The whole sequence of events, from the inrush
of calcium to the initiation of the action potential,
takes place in less than two milliseconds.
• Many of the earliest studies on chemical
synaptic transmission began with the autonomic
nervous system, but they were soon extended to
skeletal muscles when Dale and his colleagues
(1936) showed that stimulation of motor nerves
released ACh, and that ACh can induce muscle
contraction.
• The action of ACh could be increased by using a
drug, eserine, that inhibits the ACh esterase,
and the action of ACh on the muscle could be
blocked by the arrow poison, curare.
• Katz and his co-workers subsequently
used intracellular micro-electrodes to
measure the endplate potentials and
showed that these followed the release of
many vesicles of ACh, and that a similar
depolarization of the muscle occurred
when ACh was applied directly onto the
neuromuscular junction with a
micropipette.