This document discusses the neuromuscular junction. It describes the structure including the presynaptic terminal, synaptic cleft, and postsynaptic membrane containing nicotinic acetylcholine receptors. Transmission involves presynaptic calcium influx and vesicle release of acetylcholine, binding to receptors to produce an endplate potential, and hydrolysis by acetylcholinesterase. Disorders like myasthenia gravis and Lambert-Eaton syndrome are outlined. Finally, neuromuscular blockers and stimulators are classified by their mechanisms of action.

1. Neuro - muscular junction

2. • To draw the schematic diagram of Neuro-muscular junction
• To describe the events of Neuromuscular transmission
• Classify neuromuscular blockers & give mechanism of action
• Disorders of neuromuscular junction
Learning objectives

3. • Neuro-muscular junction/ Myoneural
junction
• Junction between Motor neuron & Muscle
fibre
• Action potential from nerve is transmitted
to muscle through this junction
Introduction

4. • Terminal button
• Presynaptic membrane
• Synaptic cleft
• Postsynaptic membrane
Structure

5. • Neuron innervating skeletal
muscle fibre –Motor Neurons
• Near muscle fibre it looses its myelin
sheath & divides into axon terminals
• Each terminal is expanded at its tip
to form Synaptic Knob/Terminal
Button)
Presynaptic portion- Axon terminal

6. • The motor neuron its axon, its terminal
with muscle fibre it supplies –form
MOTORUNIT
• Terminal button lies in a groove-Synaptic
Trough
• Vesicles gather at specific points –Active
Zones–Membrane at active zone modified
to form DenseBars–contains numerous
voltage gated Ca channels
Presynaptic portion- Axon terminal

7. • 50-100 nmwide
• Filled with extracellular fluid
• Contains acetyl- choline-
esterase
• It hydrolyses Ach into
Acetic acid & Choline
Synaptic cleft

8. • It’s a part of sarcolemma
• Several folds JunctionalFolds
increases membrane surface area
• Contains Ach-receptors
• voltage gatedNachannels
Post synaptic membrane

9. • Nicotinic type
• 15-40 millions/end plate
• Chemically gated ion
channels
• Contains voltage gated Na
channels& allow passage of
only Cations
Acetylcholine receptors

10. • Def–Transmission of impulses from
motor neuron to skeletal muscle
fibre.
• Mechanism 3 parts
• Presynaptic events
• Synaptic events
• Post synaptic events.
Neuromuscular transmission

11. • MainPurpose–To release acetyl choline into synaptic cleft
• Steps –
• Action potential arrive at axon terminal & Depolarize
membrane of terminal button
• Activate & open voltage gated Cachannels-Ca influx – increases
movements of Microtubules & Microfilamants- causes migration of
Neurotransmitter vesicles to pre-synaptic membrane - DOCKING
• Release acetylcholine into cleft by Exocytosis
Presynaptic events

12. • Quantal Release
• One vesicle of acetyl choline –Quanta
• Process of release of 1 vesicle is
Quantal Release
• SirKatz,Euler & Axelrod received
Nobel prize in 1970 for Quantal release
phenomenon
Presynaptic movements

13. • Binding of acetylcholine to
receptors at post synaptic
membrane
• Onthe way some are
hydrolyzed by AChE&
remaining act on receptors
Events at synaptic cleft

14. • Generate Action Potential in sarcolemma
• ACh diffuses into cleft & bind with post-
synaptic ACh receptors
• ACh Gated Ion Channels
• 5 sub uints
• When 2 molecules are attached
conformational change occurs in tubular
channels & open it & increases Na influx
Post synaptic membrane events

15. • RMPof postsynapticmembrane is -80to -90 mV
• Influx of Nachannels causes local positive potential change –END
PLATE POTENTIAL
• It’slocalized,Non-Propogated,Doesnotobey All orNoneLaw
• Butwhen critical level of -60mvreached triggers action potential in
muscle fibre in both direction
End plate potential

16. EPP
• Only 6 vesicles are required for activation from -90 to -65mv
• Each nerve impulse releases 60-125 Ach vesicles
• Every vesicle has 10,000 molecules of Ach
• 10 fold safety factor
• Action potential is always generated

17. • At rest, small quantity of acetyl
choline are released from nerve
terminal
• Each vesicle release produces
weak end plate potential about
0.5mv–MiniatureEnd Plate
Potential
Miniature end plate potential

18. • Within 1 msby 2ways
• Mostly destroyed by Ach-estarase
in synaptic cleft
• Remaining Diffuses Out of synaptic
space & no longer available for
action
• Reuptake by exchanger - Reused
Removal by ACh esterase

20. MyastheniaGravis
AutoImmune disease
Anti bodies are
produced against
Acetylcholine
Receptors & destroy
these channels
Disorders of NMJ

21. • So acetyl choline
released will not
produceadequate
endplate potential
& excite muscle
fibre
• So patient dies of
paralysis of
Respiratory
Muscles
Myasthenia gravis

22. Treatment
• Ameliorated for several hours by administering neostigmine
• Anticholinesterase drug
• Larger than normal amounts of ACh accumulate in the synaptic
space
• Within minutes, some of these paralyzed people can begin to
function almost normally

23. • Lambert-Eaton Syndrome
• Anti bodies are produced against
calciumchannels present on pre-
synaptic membrane
• Ca influx decrease & decreases
release of acetyl choline
Disorders of NMJ

24. Myasthenia gravis LEMS
Antibodies against Nicotinic
receptor for ACh in the muscle
Antibodies against Ca channels in
the nerve
Starts at eyes and moves down Starts at extremities
Weakness worsens with activity Weakness improves with activity
Associated with tumours of
thymus
Associated with Ca lung
Tt = ACh esterase inhibitor Tt = Aminopyriridines

26. What is the rationale behind the use of Calabar bean as a lie
detector by some native tribes of West Africa?
• Calabar bean - physostigmine, an AChE inhibitor
• innocent- consumes rapidly
• local gastric irritation (possibly due to accumulation of ACh
at parasympathetic postganglionic nerve endings in the
stomach) vomits
• guilty - scared & apprehensive , small sips
• suffers less gastric irritation, does not vomit, in intestines
gets absorbed

27. Summary

28. Drugs affecting NMJ

29. • Neuromuscular Blockers–
this block neuromuscular
transmission at junction.
• Curare
• Bungarotoxin
• Succinylcholine and
carbamylcholine
• Botulinum toxin
Drugs affecting NMJ

30. • Curare–active principle D-
Tubocurarine (Cobra)
• Block by combine with
Ach-receptors
• So Ach cannot act on receptors & No
End PlatePotential develop
• So these are receptor blockers
Neuromuscular blockers

31. • Bungarotoxin–
• Venomof deadly snake Krait
• Also block N-Mjunction by
combiningwith acetylcholine
receptors
Neuromuscular blockers

32. • Succinylcholine & Carbamylcholine –act like acetyl choline &
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
Neuromuscular blockers

33. • BotulinumToxin –derived from
bacteria Clostridium Botulinum
• Block the junction by preventing
the Release OfAcetyl Cholinefrom
terminal button
Neuromuscular blockers

34. • Drugs having acetylcholine like action-
• Methacholine, Carbachol & Nicotin
• But these are either not destroyed or destroyed
very slowly by acetylcholinesterase so causes
repeated stimulation & continuous action of
muscle –Muscle spasm
Neuromuscular stimulators

35. • Drugs that Inactivate the enzyme Cholinesterase
(Anticholinesterase) –Neostigmine, Physostigmine &
Disopropylflurophosphate (DFP)
• So it leads to repeated stimulation & continuous action of
muscle. E.g –Laryngeal Spasm
Neuromuscular stimulators