ANATOMY, PHYSIOLOGY OF

NEUROMUSCULAR JUNCTION
& ITS DISORDERS
DR ARPANA HAZARIKA
 Neuromuscular junction refers to the intimate contact of
nerve endings with muscle fibres to which they innervate

.
 Characteristics of the nerve and muscle fibre at the end
near the neuromascular junction
ANATOMY OF THE
NEUROMUSCULAR JUNCTION
 MOTOR UNIT: a motor neuron innervates a muscle dividing
into many nerve fibers each of which supplies 1 muscle fiber. the
combination of motor neuron & the muscle fiber it innervates is
a motor unit
 .

 SYNAPSE: is the area on the nerve lying closets to the muscle

cell, situated opposite a specialized area of the muscle cell called
endplate. The synaptic cleft is only 20nm wide
 .

 MOTOR ENDPLATE: is a small specialized area of the muscle

that is rich in Ach receptors. The surface of the muscle at the
endplate is deeply folded with many ridges & secondary clefts.
The ridges have high concentration of Ach receptors on the crest
of their folds. There are 1-10 million receptors at the endplate.
NEUROMUSCULAR JUNCTION
ANATOMY
 The NMJ consists of prejunctional motar nerve ending
separated from a highly folded postjunctional membrane of
the skeletal muscle fiber by a synaptic cleft that is 20-30 nm
wide & filled with extracellular fluid
.

 The nonmyelinated nerve endings contains

mitochondria,endoplasmic reticulum, and synaptic vesicles
necessary to synthesize the neurotransmitter acetylcholine

 The resting membrane potential of approx -90 mv across

nerve and skeletal muscle membranes is maintained by the
unequal distribution of potassium and sodium ions across the
membrane.
ANATOMY OF NMJ (CONT..)
 The NMJ contains 3 types of nicotinic cholinergic
receptors:- 2 are postsynaptic on the skeletal muscle
surface, 1 junctional and the other extrajunctional-and
one is presynaptic on the nerve ending
.

 The extrajunctional are not involved in the normal

neurotransmission but may proliferate if the skeletal
muscle is diseased, damaged, or denervated
.

 The postsynaptic receptors are concentrated on the

junctional folds, immediately opposite the sites on the
nerve endings where Ach is released.
ACETYLCHOLINE
 The neurotransmitter at the NMJ is quaternary ammonium
ester acetylcholine. Ach in motor nerve ending is synthesized
by the acetylation of choline under the control of enzyme
choline acetylase.

 Ach is stored in synaptic vesicles in the motor nerve endings

and released into the synaptic clefts as packets (quanta) each
of which contain atleast 1000 molecules of Ach
 .

 The amount of acetylcholine released by each nerve impulse

is large, at least 200 quanta of about 5000 molecules each,
and the number of AChRs activated by transmitter released
by a nerve impulse is also large, about 500,000 molecules.
ACETYLCHOLINE
 There seem to be two pools of vesicles that release
acetylcholine, a readily releasable pool and a reserve
pool, sometimes called VP2 and VP1, respectively

 Arrival of nerve impulse causes the opening of calcium

channels & Ca enters the nerve terminal & there is Ca
dependant synchronous release of hundreds of quantas of
Ach that bind to nicotinic cholinergic receptors on the
postsynaptic membrane causing a change in the
membrane permeability to ions.
ACETYLCHOLINE (CONTI..)
 Ach receptors bind to the pentameric complex & induce a
conformational change in the proteins of the alpha subunits which
open the channel & K ion leaks outside whereas Na ion moves inside
 .

 Inside the cell the resting membrane potential is -90mv.Na ions are
attracted to the inside of the cell which induces depolerization. Once
the threshold of -50mv is reached voltage gated Na channels on the
sarcolemma are opened & allow the flow of Na ions into the muscle.
This increases the rate of depolerization forming AP that passes
around the whole sarcolemma causing muscle contraction.

 In the absence of AP, quanta of Ach are released randomly producing

miniature endplate potentials of <1mv that are insufficient to trigger
depolerization of the skeletal muscle membrane.
NERVE ACTION POTENTIAL
 Nerve signals are transmitted by action potentials which are
rapid changes in the membrane potential.
 STAGES:

 Resting stage: before the action potential. The membrane is

said to be polerised because of large negative memb potential
that is present.
 Depolerization stage: the memb becomes permeable to Na
ions allowing a large no of positively charged Na ions to flow
into the interior of the axon.The normal polerised state of
-90mv is lost & potential rises rapidly in the positive
direction, this is called depolerisation.
NERVE ACTION POTENTIAL
 Repolerization stage: within a few seconds after the
membrane has become permeable to Na ions the Na
channel begins to close& K channel open more than they
normally do. The rapid diffusion of K ions to the exterior
re-establishes the normal negative resting membrane
potential.
. A, THE ION CHANNEL IS INACTIVE AND DOES NOT OPEN IN THE ABSENCE OF
ACETYLCHOLINE. B, EVEN BINDING OF ONE ACETYLCHOLINE MOLECULE (FILLED
CIRCLE) TO ONE OF TWO BINDING SITES DOES NOT OPEN THE CHANNEL. C,
WHEN ACETYLCHOLINE BINDS TO THE RECOGNITION SITES OF BOTH Α-
SUBUNITS SIMULTANEOUSLY (FILLED CIRCLES), A CONFORMATION CHANGE IS
TRIGGERED THAT OPENS THE CHANNEL AND ALLOWS IONS TO FLOW ACROSS
THE MEMBRANE
ACETYLCHOLINE (CONT..)
 It is speculated that nerve AP activates adenylate cyclase in membranes of
nerve terminals leading to formation of cyclic adenosine monophosphate
(cAMP).cAMP subsequently opens Ca ion channels causing synaptic
vesicles to fuse with nerve membrane & release Ach
.

 Situated in close proximity is enzyme acetylcholinesterase.

Acetylcholinesterase at the junction is the asymmetric or A12-form protein
made in the muscle, under the end plate. It is a type B carboxylesterase
enzyme. There is a smaller concentration of it in the extrajunctional area.


 The enzyme is secreted from the muscle but remains attached to it by thin
stalks of collagen fastened to the basement membrane This enzyme is
responsible for the rapid hydrolysis of Ach in <1ms to acetic acid & choline.
 Choline then re-enters motor nerve endings to again participate in the
synthesis of new Ach.
NICOTINIC RECEPTORS CONT..
 Nicotinic cholinergic receptors extend throughout the
skeletal muscle membrane and approx 2nm into the
cytoplasm. The subunits of the receptor are assembled
like barrel staves into cylindrical receptors which has a
central funnel shaped core, so as to form a channel to
allow the flow of ions along a concentration gradient
.

 Each NMJ contains millions of postjunctional receptors

& a burst of Ach from the nerve ending open atleast
400,000 recptors. As a result sufficient flow through
these receptors to depolarize the endplate to create AP.
DIAGRAM
EXTRAJUNCTIONAL & PREJUNCTIONAL
CHOLINERGIC RECEPTORS
 They are not present in large numbers as their synthesis
is supressed by neural activity. Whenever motor nerve
are less active due to trauma or denervation they
proliferate

 The prejunctional receptors differ from the

postjunctional nicotinic receptors in 1) chemical binding
characteristics 2) the nature of the ion channel they
control 3) their preferential blockade during high
frequency stimulation.
NEUROMUSCULAR DISORDERS
 MYASTHENIA GRAVIS:
 It is an NM disorder affecting the NMJ & it is characterized
by impaired neuromuscular transmission & muscle
weakness.Prevalence is 1/20000-30000. F/M ratio is 6:4. Age:
any age Most patients have circulating autoantibodies to the
postsynaptic nicotinic Ach receptors. A thymoma is found in
approx 10% of patients & hyperplasia of the thymus is found
in young patients, although the precise etiology is unknown.
1. Features : weakness on exertion that improves with rest.

2. Ocular, bulbar & facial muscles are commonly involved-

ptosis, reduced facial expression,dysarthria & dysphagia.
NMJ- DISORDERS…
 Limb weakness, when present is usually proximal, &
weakness of the small muscles of the hand may occur.
 Myasthenia may be unmasked by anesthesia which
may result in hypoventilation or apnoea postop.
Treatment: *oral anticholinesterases-pyridostigmine
*Immunosupression-corticosteriods or azathioprine
*Thymectomy – young onset, AB positive pt, thymoma.
*Plasmapheresis .
EATON –LAMBERT SYNDROME
Eaton-Lambert myasthenic syndrome (ELMS) is an
immune-mediated channelopathy caused by
decreased release of acetylcholine as a result of
autoantibodies against presynaptic voltage-gated
calcium channels and other presynaptic elements.
 Patients with ELMS have muscle weakness and
fatigability, generally of the proximal limb muscles,
with the lower extremities affected more often than
the extraocular and bulbar muscle groups. The
syndrome is frequently part of a paraneoplastic
phenomenon, usually combined with small cell lung
carcinoma.
EATON-LAMBERT SYNDROME
 Patients with ELMS are usually worse in the morning
with gradual improvement throughout the day.
Improvement of muscle function with exercise is due to
the accumulation of presynaptic calcium and subsequent
improved release of acetylcholine.
 The diagnosis of ELMS is made by careful physical
examination combined with clinical electrophysiology
showing the typical facilitation with high-frequency nerve
stimulation (30 to 50 Hz). Anticholinesterase treatment
has little effect on patients with ELMS. Plasmapheresis,
immunoglobulin therapy, and 3,4-diaminopyridine (DAP)
result in transient improvement.
DRUGS AFFECTING NEUROMASCULAR JUNCTION

NEUROMASCULAR BLOCKERS
Neuromascular blockers are the drugs that block
transmission at the neuromascular junction.Some
common neuromascular blockers
CURARE_curare or the active principle of D-
Tubocurarine prevents the neuromascular
transmission by combining with acetylcholine
receptors,The acetyllcoline released cannot
combine with receptors and so end plate potential
BUNGAROTOXIN-found in the venom of deadly
snakes also blocks neuromascular transmission
by binding with acetylcholine receptors

SUCCINYL CHOLINE AND

CARBANYLCHOLINE-act like acetyl choline and
cause depolarisation of post synapticmembrane.But
these are not destroyed by cholinisterase and the
muscle remains in a depolarised state for a long
time,These drugs block the myoneural junction by
keeping the muscle in depolarised state.
Botulinium toxin-is derived from the bacteria-
clostridium botulinism.It blocks transmission
across the myoneural junction by preventing the
release of acetyl choline from the terminal button
of nerve ending,
NEUROMASCULAR STIMULATOR-

The drug methacholine,carbachol and nicotine

Act like acetylcholine and produce end plate
potential exciting muscle fibres.These drugs are
either not destroyed or destroyed very slowly so
they can cause repeated stimulation
 Drugs like neostigmine,physostigmine and disopropyl
fluorophosphate stimulate neuromascular junction by
inactiviting cholinisterase enzyme.
THANK YOU….