The neuromuscular junction is the synapse between a motor neuron and a muscle fiber. It consists of a presynaptic terminal, synaptic cleft, and postsynaptic membrane. An action potential in the motor neuron causes acetylcholine release into the cleft from vesicles. Acetylcholine binds nicotinic receptors on the muscle fiber, generating an endplate potential that depolarizes the fiber and initiates an action potential if the threshold is reached. Acetylcholine is then broken down by acetylcholinesterase to terminate the signal. Disorders can occur if antibodies attack receptors or calcium channels, impairing signal transmission and causing weakness.

1. NEUROMUSCULAR
JUNCTION
PRESENTOR-
Dr.K.AMUDHALAKSHMIM.B.B.S.,D.O.,M.D

2. INTRODUCTION
HISTORY
STRUCTURE
NEUROMUSCULAR TRANSMISSION
INITIATION OF ACTION POTENTIAL
APPLIED ASPECTS
SUMMARY
REFERENCES
SYNPOSIS

3. INTRODUCTION
Also called Myoneural
junction/Motor end plate
Junction between motor
neuron and muscle fibre.
An modified synapse.
Each nerve fibre-many
terminal branches- 2μm
diameter
Terminals-covered by
schwann cells- Teloglia
Each terminal branch
innervates one muscle fibre
Action potential from nerve
is transmitted to muscle
through this junction

4. HISTORY
NMJ First described- Crustacean species-The
Crayfish
T.H.Huxley in 1879

5. Quantal release phenomenon
Sir katz, Euler & Axelrod received nobel prize in
1970
Bernard Katz Ulf Von Euler Julius Axelrod

6. Charles Scott Sherrington
Neurophysiologist
Discovered synapse
Father of Synaptic transmission
Father of Neurophysiology

7. STRUCTURE
Terminal button
Pre synaptic membrane
Synaptic cleft
Post synaptic membrane

8. PRE SYNAPTIC PORTION-
AXON TERMINAL
• Neuron innervating skeletal muscle fibre-motor
neurons
• Near muscle fibre it looses its myelin sheath &
divides into axon terminals
• Each axon terminal is expanded at its tip to form
synaptic knob(terminal button or axon
telodendria)
• The motor neuron, its axon ,its terminal with
muscle fibre it supplies- form Motor Unit

9. • Terminal button lies in a
groove- Synaptic Trough
or Synaptic gutter.
• Axon terminal-
mitochondria & vesicles.
• Vesicles gather at specific
points-contain Ach-Active
zones
• Dense bars- modified
membrane at active
zones, contains numerous
voltage gated Ca2+
channels

10. SYNAPTIC CLEFT
• 50-100 nm wide
• Filled with extracellular
fluid
• Muscle fibre is covered by
basement membrane or
basal lamina
• It contains Acetylcholine
esterase
• It hydrolyses Ach into
Acetate & inactive Choline

11. POST SYNAPTIC MEMBRANE (END
PLATE MEMBRANE)
• Its a part of sarcolemma &
lies under terminal button
• It is thrown into several
folds- Junctional
Folds/Pallisades
• Increases end plate
membrane surface area
• Contain Ach-receptors
which contains ligand
gated Na+ channels

12. ACETYL CHOLINE RECEPTORS
• Nicotinic type
• 15-40 millions/end plate
• 10,000 AchR/square micrometer
• Chemically or Ligand gated ion channels
• Blocked by Bungarotoxin
• Post synaptic membrane also contains voltage
gated Na+ channels & allow passage of only
cations.

13. • Na+ channels – voltage sensitive
depolarisation
• Na+ channels open at -55 mV
• Calcium channels open at -40mV

14. NEUROMUSCULAR TRANSMISSION
• Transmission of impulses from motor neuron to
skeletal muscle
• Mechanism 3 parts
Pre synaptic events
Synaptic events
Post synaptic events

15. PRE-SYNAPTIC EVENTS
Main purpose-to release Acetyl choline into
synaptic cleft
STEPS
1. Action potential arrive at axon terminal &
depolarize membrane of terminal button
2. Activates and open voltage gated Ca2+ channels-
Ca2+ influx-increases movements of
microtubules & microfilaments-causes
migration of neurotransmitter vesicles to pre
synaptic membrane- Docking
3. Release acetylcholine into cleft by exocytosis.

16. Exocytosis of Ach requires:
Ca2+ ions
Fusion of vesicle to the
membrane requires-
Synaptobrevin-SNARE
protein-vesicular
membrane protein
Syntaxin-neuronal
membrane protein
SNAP-25,α/ϒ SNAP,NSF
and other proteins.

17. QUANTAL RELEASE
• One vesicle of acetyl choline-quanta
• Process of release of 1 vesicle is quantal release
• Sir Katz, Euler & Axelrod received nobel prize in
1970 for quantal release phenomenon.
• One vesicle- 40 nm size
Golgi apparatus in cell body
3 lakhs vesicles
10,000 Ach molecules.
• 125 vesicles open at a time, to release Ach

18. SYNAPTIC CLEFT EVENTS
• Main purpose-binding of
acetylcholine to receptors
at post synaptic
membrane.
• On the way some are
hydrolyzed by
Acetylcholine esterase &
remaining act on
receptors.

19. POST SYNAPTIC EVENTS
• Main purpose – generate action potential in
sarcolemma
• 5-10 milliseconds
• Acetylcholine diffuses into cleft and bind with
post synaptic acetylcholine receptors.
• Receptors are Acetylcholine gated ion channels
• Ion channels has 5 sub units.
• When two molecules of Ach are attached,
conformational change occurs in tubular
channels & open it & increases Na+ influx.

20. STRUCTURE OF ACETYCHOLINE
• Ach-molecular weight-2,75,000 daltons.
• 5 sub-units.
• 2 alpha,1 beta,1 delta and1 gamma

21. DEVELOPMENT OF END PLATE
POTENTIAL
• RMP of post synaptic
membrane is -80 to -90 mv
• Influx of Na+ channels
causes local positive
potential change-END
PLATE POTENTIAL
• It is localized, non-
propagated, does not obey
all or none law.
• But when critical level of -
60 mv reached triggers
action potential in muscle
fibre in both direction.

22. ACTION POTENTIAL
• Propagative
• Long distance signal
• Both depolarization and
repolarisation
• Obeys all or none law
• Summation is not
possible
• Has refractory period
END PLATE
POTENTIAL/GRADED
POTENTIAL
• Non propagative
• Short distance signal
• Only depolarization or
hyperpolarisation
• Does not obey all or
none law
• Summation is possible
• No refractory period

23. MINIATURE ENDPLATE POTENTIAL
• At rest, small quantity of
acetylcholine are released
from nerve terminal.
• Each vesicle released
produces weak end plate
potential about 0.5 mv –
Miniature end plate
potential

25. Resting membrane
Potential (mV)
Duration of action
Potential (milliseconds)
Velocity of
Conduction (m/second)
Nerve action Muscle
potential action potential
-70 -80 to -90
0.2-0.3 1-5
70-120 3-5
COMPARISON OF ACTION POTENTIAL

26. REMOVAL OF ACETYCHOLINE BY
CHOLINESTERASE
• Within 1 millisecond by 2
ways
• Mostly destroyed by
Acetylcholine esterase in
synaptic cleft.
• Remaining diffuses out of
synaptic space & no longer
available for action.
• It prevents repeated
excitation of the muscle
fibre.
• Allows muscle to relax.

27. REUPTAKE PROCESS
• Degraded product of
neurotransmitter re-enters
pre synaptic axon terminal-
reused
• Through Vesicular
acetylchonine transporter
(SLC18A3 gene in intron of
choline acetyltransferase)
• Acetylcholine esterase
degrades Ach inactive
choline + acetate
• Choline- Taken back to axon
terminal.
• Reused to form new
acetylcholine molecule.

28. INITIATION OF THE ACTION POTENTIAL
IN MUSCLE FIBRE

29. MOTOR UNIT
Single motor neuron, its
axon terminals and muscle
fibres innervated by it.
Fine, graded and precise
movements- number of
muscle fibres are small. Eg-
laryngeal muscles,
pharyngeal muscles, ocular
muscles.
Crude & coarse movements-
number of muscle fibres are
large.
Each motor unit innervates
120 to 165 muscle fibres.
Eg- muscles of leg & back.

30. RECRUITMENT OF MOTOR UNIT
Weak strength stimulus- few motor units
involved.
Strong strength stimulus – many motor units
involved.
Recruitment of motor unit- more & more
motor unit put into action
Graded response- directly proportional to
number of motor units activated.
Studied by- Electromyography

31. DRUGS AFFECTING NEUROMUSCULAR
JUNCTION
• Neuromuscular blockers- blocks neuromuscular
transmission at junction
Curare
Bungarotoxin
Succinycholine and
Carbamylcholine
Botulinum toxin

32. NEUROMUSCULAR BLOCKERS
Curare- Active principle D-
Tubocurarine (cobra)
Arrow head poisoning
for hunting
Block by combining
with Ach-receptors.
So Ach cannot act on
receptors & no end plate
potential developed
So these are receptor
blockers

33. • Bungarotoxin - Venom of deadly snake(krait)
Also block N-M Junction by
combining with acetylcholine receptors.
• Succinylcholine & carbamylcholine- act like
acetylcholine & depolarizes post synaptic
membrane.
But these are not destroyed by
cholinesterase- so muscle remain in depolarized
state for a long time
So these block myoneural junction by
keeping the muscle in depolarized state for long
time.

34. • Botulinum toxin- derived from bacteria
Clostridium botulinum
Synaptobrevin degraded by botulinium
toxin
Block the NMJ by preventing the release of
acetylcholine from terminal button
no muscle contraction
flaccid paralysis
Used therapeutically-Achalasia cardia,
Strabismus, Blepharospasm, Cervical dystonia
Lethal Bioterrorism agent

35. Tetradoxin
Puffer fish
Blocks voltage gated
Na+ channel
Respiratory muscle
paralysis.
Death

36. NEUROMUSCULAR STIMULANTS
• Drugs having acetylcholine like action
Methacholine, Carbachol & Nicotine
• But these are either not destroyed or
destroyed very slowly by Acetyl
cholinesterase, so causes repeated stimulation
& continuous contraction of Muscle- Muscle
spasm.

37. • Drugs that inactivate the
enzyme Cholinesterase
(Anticholinesterase) –
Neostigmine,
physostigmine &
Disopropylflurophsphate
(DFP-nerve gas)
So it leads to
repeated stimulation &
continuous action of
muscle
Eg- Laryngeal spasm.

38. ORGANOPHOSPHOROUS POISONING
• Acetylcholine esterase inhibited-irreversible
• Ach increases in synaptic cleft
• Sustained depolarization of end plate
• Skeletal muscle paralysis
• Death- asphyxiation
• Pupil-pin point
• Secretions increases.
• Atropine -antidote

39. DISORDERS OF NEUROMUSCULAR
JUNCTION
• Myasthenia gravis- Autoimmune disease.
Antibodies are produced against nicotinic
acetylcholine receptors & destroy these channels

40. • So acetylcholine released will not produce
adequate end plate potential & excite muscle
fibre
• So patient dies of paralysis of respiratory
muscles.

41. Lambert- Eaton syndrome
• Antibodies are produced
against voltage sensitive
calcium channels present
on pre-synaptic membrane
• so Ca2+ influx decreased
• decreases release of
acetylcholine
• Muscle weakness-limb
muscles
• Incremental response to
repetitive nerve
stimulation as calcium level
raises

42. LAMBERT- EATON SYNDROME
• Antibodies against the
voltage gated Ca2+
channels in nerve.
• Starts at extremities
and moves up
• Weakness improves
upon activity
• Associated with small
cell lung cancer.
• Therapy-
Aminopyridines
MYASTHENIA GRAVIS
• Antibodies against the
Nicotinic Ach receptor
for acetylcholine in
muscle.
• Starts at eyes and
moves down
• Weakness worsens
upon activity
• Associated with
Thymoma
• Therapy-Acetylcholine
esterase inhibitors.

43. SUMMARY

44. REFERENCES
• Guyton and Hall- Text Book of Medical Physiology-13th
International edition.
• Ganong ‘s Review of Medical Physiology 26th edition.
• Text book of medical Physiology- Indhu Khurana 2nd
edition
• Comprehensive Text Book of Medical Physiology- G.K. Pal
2nd edition
• Berne & Levy-Text book of Medical Physiology 1st edition
• Boron-Text book of Medical Physiology 3rd edition
• Sharada Subramaniam- Text book of Medical Physiology
7th edition
• Chatterjee- Textbook of human physiology- 13th edition