ANATOMY AND PHYSIOLOGY OF

NEUROMUSCULAR JUNCTION

Under the guidance of : Presented by:

Dr. Sara Mary Thomas Dr. Paras Anand
(Professor) (1st year Resident)
Department of Department of Anaesthesiology
Anaesthesiology S.B.K.S.M.I.&R.C.
S.B.K.S.M.I.&R.C.
NEUROMUSCULAR JUNCTION

The neuromuscular junction is a synapse that develops

between a motor neuron and a muscle fiber and is made up
of several components:
• presynaptic nerve terminal
• Synaptic cleft / junctional cleft ( 50 nm )
• postsynaptic muscle membrane
• motor neuron runs without interruption from the
ventral horn of the spinal cord or medulla to the
neuromuscular junction as a large, myelinated
axon as the motor neuron approaches the muscle,
the neuron repeatedly branches to contact many
muscle cells and gather them into a functional
group known as a motor unit
• As the terminal reaches the muscle fiber, it loses
its myelin, forms a spray of terminal branches
against the muscle surface, and is covered by
Schwann cells.
• The nerve is separated from the surface of the
muscle by a gap of approximately 50 nm, called
the junctional cleft or synaptic cleft
The nerve and muscle are held in tight alignment
by protein filaments called basal lamina that span
the cleft between the nerve and end plate. The
muscle surface is heavily corrugated, with deep
invaginations of the junctional cleft—the primary
and secondary clefts
• Nicotinic acetylcholine receptors (nAChRs) are located at pre- and
postjunctional sites.
• Neuromuscular transmission is initiated by arrival of an impulse at the
motor nerve terminal with an associated influx of calcium ions and
resultant release of the ligand ACh.
• ACh binds to AChRs (the ligand-gated channel) on postjunctional
membranes and thereby causes a change in membrane permeability to
ions, principally potassium and sodium.
• This change in permeability and movement of ions causes a decrease in
the transmembrane potential from about -90 mV to -45 mV (threshold
potential), at which point a propagated action potential spreads over the
surfaces of skeletal muscle fibers and leads to muscular contraction. ACh
is rapidly hydrolyzed (within 15 ms) by the enzyme acetylcholinesterase
(true cholinesterase), thus restoring membrane permeability
(repolarization) and preventing sustained depolarization.
• Acetylcholinesterase is primarily located in the folds of the end-plate
region, which places it in close proximity to the site of
action of ACh.
• The large intracellular structures are
mitochondria. Acetylcholine (ACh), synthesized
from choline and acetate by acetyl coenzyme A
(CoA), is transported into coated vesicles,
which are moved to release sites.
• A presynaptic action potential that triggers
the influx of calcium (Ca2+) through
specialized proteins (i.e., Ca2+ channels)
causes the vesicles to fuse with the membrane
and discharge transmitter. Membrane from the
vesicle is retracted from the nerve membrane
and recycled. Each vesicle can undergo various
degrees of release of contents—from
incomplete to complete. The transmitter
is inactivated by diffusion, catabolism, or
reuptake.
• The inset provides a magnified view of a
synaptic vesicle. Quanta of ACh, together with
adenosine triphosphate (ATP), are stored in
the vesicle and covered by vesicle membrane
proteins. Synaptophysin is a glycoprotein
component of the vesicle membrane.
Synaptotagmin is the vesicle’s calcium sensor.
Phosphorylation of another membrane protein,
synapsin, facilitates vesicular trafficking to the
release site. Synaptobrevin (vesicle-associated
membrane protein [VAMP]) is a SNARE protein
involved in attaching the vesicle to the
release-site proteins at the nerve terminal
• The immature, extrajunctional, or fetal form consistsof two
α1-subunits and one each of β1-, δ-, and γ-subunits.
• Its called the γ-subunit receptor. A neuronal receptor
consisting of five α7-subunits has been described in muscle.
All the subunits are arranged around the central cation
channel. The immature isoform containing the γ-subunit has
long open times and low-amplitude channel currents.
• The mature or junctional receptor consists of two α1-
subunits and one each of β1-, δ-, and ε-subunits.
• The mature isoform containing the ε-subunit has shorter
open times and high-amplitude channel currents during
depolarization. Substitution of the ε-subunit for the γ-
subunit gives rise to the fast-gated, high-conductance
channel type.
• application of acetylcholine to the α7 AChR also results in
a fast, rapidly decaying inward current. All these
depolarizing events are insensitive to treatment with
muscarinic acetylcholine receptor antagonist, atropine, but
sensitive to treatment with α-bungarotoxin or muscle
relaxants, which block the flow of current. The affinity of
the muscle relaxants to each of the three isoforms may be
different, α7 AChR being the least sensitive to block.
PREJUNCTIONAL RECEPTORS
EXTRA JUNCTIONAL RECEPTOR
ACH ( SYNTHESIS , STORAGE , RELEASE )
ACTION POTENTIAL
• Skeletal muscle blood flow can increase more than 20 times during
strenuous exercise. The increase in cardiac output that occurs during
exercise results from local vasodilation and subsequent increase in
venous return of heart.
• Among inhaled: isoflurane- increase in skeletal muscle blood flow-
potent vasodilator
Smooth muscle

• Smooth muscle contraction is controlled exclusively by nerve signals.

• Spontaneous contractions rarely in ciliary muscle, iris and smooth muscle of many large blood vessels.
• Smooth muscle cells lack T- tubules that provide electrical link to sarcoplasmic reticulum.
• Calcium ion channels include ryanodine receptors and IP3 gated calcium ion channels.
• Visceral smooth muscle is characterized by cell membranes that contact adjacent cell membranes forming a
functional syncytium that undergoes spontaneous contractions as a single unit in the absence of nerve
stimulation.( peristaltic motion in bile duct, ureter)

• In the absence of extrinsic innervation, smooth muscles are unique in their sensitivity to hormones like muscle
spasm may persist for hours in response to norepinephrine and local factors such as lack of oxygen cause
vasodilation.
Mechanism of smooth muscle
contraction
• Contain both actin & myosin but lacks troponin.
• Calcium that causes contraction enters from ECF at the time of action
potential & pump is slow compared to sarcoplasmic reticulum.
• Contraction of smooth muscle is in seconds & skeletal muscle is in
milliseconds.at some
• Two neurotransmitters : acetylcholine & norepinephrine are secreted by
the ANS that innervate smooth muscles.
• Ach is an excitatory neurotransmitter for smooth muscle at some sites
& inhibitory for other sites.
• Norepinephrine exerts reverse effects of Ach.
STRUCTURE OF SODIUM CHANNEL
ROLE OF CALCIUM
ACETYLCHOLINESTERASE
 PHYSICAL CHANNEL BLOCKADE

• OPEN CHANNEL • CLOSED CHANNEL

BLOCK BLOCK
Neuromuscular blockers
• All are quaternary ammonium compounds & structurally related to
Ach.
• Mostly drugs that are used are synthetic alkaloids.
 Enzymes

Acetylcholinesterase Buterylcholinesterase
True pseudo
Present in NMJ Synthesize in liver & mainly in plasma
Responsible for rapid hydrolysis of Ach Catalyse the hydrolysis of Sch
Ach to acetic acid & choline
TOF
Characteristics
• Decrease in twitch tension
• Fade during repetitive stimulation (TOF or tetanic)
• TOF- four stimuli delivered every 0.5 second
• Post tetanic potentiation
Depolarizing neuromuscular blocker
• Sch, which is structurally 2 molecules of Ach bind together.
• Partial agonist of nAchR & depolarizes the ion channels.
• It is not hydrolysed by acetylcholinesterase, so channel remains open
for a longer period of time resulting in a depolarizing block.( sustain
depolarization prevents propagation of AP.(membrane
hyperpolarization).
Characteristics
• Depolarizing neuromuscular block( phase 1 block):
Inhibition of nerve impulse transmission across the myoneural junction
associated with depolarization of the motor endplate.

• Often preceded by muscle fasciculation

• Decrease in twitch tension
• No fade during repetitive stimulation (tetanic or TOF)
• No post tetanic potentiation
 Phase II block:
• Seen after repeated dosing
• Infusion (50-60mcg/kg/min for 30-60min)
• A single large bolus (5-7 mg/kg) of Sch
results in a prolonged duration of block, resembling non depolarizing
blockade on monitoring and is unresponsive to Ach even if repolarized.
 Mechanism of phase II block
• Repeated end plate depolarization causing ionic imbalance of NMJ ( repeated sodium
influx and potassium efflux) and altered membrane function
• Desensitization due to continuous presence of agonist at site of action
• Pre-junctional receptor inhibition with decreased Ach release
• Calcium entry via opened channel resulting in disruption of receptors and end plate
elements
• Patients with atypical plasma cholinesterase may develop phase II block even with usual
doses of Sch.
• Potentiated by inhalational agents(enflurane, isoflurane etc)
• Management of phase II block:
• Ventilate the patient till TOF ratio has recovered to 0.9 or more
• Reversal with anticholinesterases is not recommended as they do not consistently result
in adequate antagonism of neuromuscular blockage.
THANK YOU