All about Neuromuscular junction...Structure,Steps involved,Drugs acting at neuromuscular junction , Clinical aspects (Myasthenia gravis and lambert eaton syndrome)
2. OBJECTIVES
Structure of Neuromuscular junction
Events occurring at Neuromuscular
junction
Drugs acting on Neuromuscular
junction and their mechanism of action
Clinical Aspects
1)Myasthenia Gravis
2)Lambert-Eaton Syndrome
3. First of all….What is a
neuromuscular junction??
Neuromuscular junction refers to the
intimate contact of nerve endings with
the muscle fiber to which they innervate
The following structures are included in a
typical neuromuscular junction
* Terminal button
* Presynaptic membrane
* Synaptic cleft
* Postsynaptic membrane
4. 1) Terminal Button
The axon of a neuron supplying a
skeletal muscle loses its myelin sheath
and divides into a number of fine
branches which end in small knobs
called terminal buttons or end feet which
forms a neuromuscular junction, at the
centre of muscle fibre .
Synaptic knob contain about three lakh
vesicles containing acetylcholine and
mitochondria.
The acetylcholine is synthesized by the
mitochondria and is stored in the
vesicles
5. Pre synaptic membrane
This refers to the axonal membrane
lining the terminal buttons of the nerve
endings.
6. Synaptic cleft
It is the space between the
presynaptic and the postsynaptic
membrane
It is about 50-100nm
It is filled with ECF with reticular fibers
forming the matrix
7. Post synaptic membrane
It refers to the sacrolemma of the
muscle fiber which is present in the
neuromuscular junction
The sacrolemma is thickened and
depressed to form the synaptic trough
where the terminal button fits
This thickened portion is called the
motor end plate
8. Contd…
The postsynaptic membrane contains
receptor sites for ACETYLCHOLINE
called as the NICOTINIC
RECEPTORS
The matrix of cleft contains the
enzyme CHOLINESTERASE which
hydrolyzes the acetylcholine
11. Synthesis of
ACETYLCHOLINE
Raw materials :
The mitochondria requires
Choline
Acetyl Co Enzyme-A
ATP
Glucose
Enzyme---} Choline acetylase (or)
Choline transferase
12. Storage :
Acetylcholine once synthesized is
stored temporarily in the vesicles in
small packets called quanta which
consists of about 10^4 molecules of
acetylcholine
13. Sequence of events:
Release of acetylcholine by the nerve
terminals
Effect of acetylcholine on the
postsynaptic membrane
Development of end plate potential
Miniature end plate potential
Removal of acetylcholine by
cholinesterase
Initiation of action potential in the muscle
fiber
14. Release of acetylcholine by the
nerve terminals
When the nerve impulse travelling in the
nerve fibre (axon) reaches the terminal
buttons, the voltage gated Ca2+
channels present on the presynaptic
membrane open up, increasing its
permeability to Ca2+ ions.
Consequently, the Ca2+ ions present in
the ECF of the synaptic cleft enter the
cytosol of the terminal buttons which
inturn trigger a marked increase in
exocytosis of vesicles releasing
15. Effect of acetylcholine of the
postsynaptic membrane
The acetylcholine so released diffuses
in the synaptic cleft and binds to the
nicotinic–acetylcholine receptors
located mainly on the junctional folds
of the motor end plate (postsynaptic
membrane) leading to opening up of
the tubular channels.
16. Development of end plate
potential
Due to opening of the acetylcholine-
gated channels in the end plate
membrane, a large number of Na+
ions from the ECF enter inside the
muscle fibre causing a local positive
potential change inside the muscle
fibre membrane called the end plate
potential.
17. Contd…
The end plate potential is non-
propagative but when a critical level of
−60 mV is reached, it triggers the
development of action potential in the
muscle fibre
The action potentials are generated on
either side of the end plate and
conducted away from the end plate in
both the directions along the muscle
fibres thus causing muscle contraction
19. Miniature end plate potential
Even at rest, small quanta of
acetylcholine are released randomly
from the nerve terminal because of
random Brownian movement of
axoplasm.
Each quantum of acetylcholine
produces a weak end plate potential
about 0.5 mV in magnitude. This is
called miniature end plate potential.
20. Giant end plate potential
Due to increased releasing of
Acetylcholine the end plate potential
rises to 12mV.
This is known as giant end plate
potential
This is not sufficient to generate
action potential
21. Removal of acetylcholine
The acetylcholine released in the
synaptic cleft stays for a short time
and is removed within 1 ms by the
enzyme acetylcholinesterase present
in the matrix of synaptic cleft.
A small amount of ACh diffuses back
into nerve terminals from the synaptic
cleft.
The rapid removal prevents repeated
excitation of the muscle fibre
22. Drugs affecting neuromuscular
juncton
These drugs are classified as :
*Drugs which block transmission,
known as NEUROMUSCULAR
BLOCKERS
*Drugs that stimulate transmission,
the NEUROMUSCULAR
STIMULATORS
24. Curare
Curare combines with the
aceytlcholine receptors
Thus there will be no sites for the
acetylcholine to combine and hence
end plate potential will not develop
This is the active principle of
D-tubocurarine
26. Bungarotoxin
This is obtained from venom of deadly
snakes
This also binds with the Acetylcholine
receptors and block the transmission
27. Obtained from a krait (snake)
Bungarus multicinctus
Courtesy: PubChem and
Thomas Brown
28. Succinylcholine &
carbamylcholine
Succinylcholine and carbamylcholine
act like acetylcholine and cause
depolarization of the postsynaptic
membrane.
But, these are not destroyed by
cholinesterase and so the muscle
remains in a depolarized state for a
long time.
Thus, these drugs block the
myoneural junction by keeping the
31. Botulinum toxin
It is obtained from Clostridium
botulinum
It prevents the release of acetylcholine
from the terminal branches of the
nerve endings
33. Neuromuscular stimulators
• Methacholine
• Carbachol
• NicotineDrugs acting
like Ach
• Neostigmine
• Physostigmine
• Diisopropyl
flurophosphate(DFP)
Drugs that
inactivate
cholinesterase
34. Drugs acting like Ach
These act like acetylcholine and
produce end plate potential exciting
the muscle fibre.
However, these drugs are either not
destroyed or are destroyed very slowly
by the enzyme acetylcholinesterase.
So they cause repeated stimulation
and continuous action of muscle,
thereby causing a state of muscle
spasm.
35. Drugs that inactivates the
enzyme cholinesterase:
These stimulate the neuromuscular
junction by inactivating this enzyme due
to which the acetylcholine released at
the nerve terminal cannot be hydrolysed,
this leads to repeated stimulation and
continuous action of muscle.
The effect of neostigmine and
physostigmine lasts for several hours
while that of DFP lasts for several
weeks.
The DFP is thus a lethal poison which
can cause death due to laryngeal spasm.
39. Lambert-Eaton syndrome
Here, antibodies are produced against
the calcium channels present on the
presynaptic membrane which destroy the
channels.
Consequently, Ca2+ influx into the nerve
terminal is markedly decreased and
thereby release of acetylcholine is also
reduced.
Scanty amount of acetylcholine is not
able to produce adequate end plate
potential to excite the muscle fibres
producing muscular weakness.
40. Symptoms
Weak muscles – weakness is often
relieved temporarily after exercise or
exertion
Trouble walking
Tingling sensation in the hands or feet
Eyelid drooping
Fatigue
Dry mouth
Trouble speaking and swallowing
Trouble breathing
Bladder and bowel changes
Erectile dysfunction
41. References:
Medical physiology for Undergraduate
students by Indu Khurana 1st Edition
Textbook of Medical physiology by
Guyton and Hall , 2nd South Asia
Edition
Johns Hopkins Medical library(online)