7&8- The Neuromuscular Junction & Physiology of Skeletal Muscle Contraction .ppt

The Neuromuscular Junction & Physiology of Skeletal Muscle Contraction

1. The Neuromuscular JunctionThe Neuromuscular Junction
( Neuromuscular Synapse )( Neuromuscular Synapse )

2. Know and describe the followings:
The physiologic anatomy of the skeletal muscle and NM junction.
Motor End Plate potential and how action potential and excitation-
contraction coupling are generated in skeletal muscle.
' Explain the pathophysiology and classification of Myasthenia Gravis
(MG)
• List the signs and symptoms and clinical manifestation
• Describe the various treatments available for Myasthenia Gravis
• Discuss the anesthetic considerations for patients with M Gravis
Objectives of the lecture
At the end of the lecture the student should be able to:

3. Chemical SignalsChemical Signals

One neuron will transmit info to another neuron or to a One neuron will transmit info to another neuron or to a
muscle or gland cell by releasing chemicals called muscle or gland cell by releasing chemicals called
neurotransmitters.neurotransmitters.

The site of this chemical interplay is known as the The site of this chemical interplay is known as the synapsesynapse..

An axon terminal (An axon terminal (synaptic knobsynaptic knob) will abut another cell, a neuron, ) will abut another cell, a neuron,
muscle fiber, or gland cell.muscle fiber, or gland cell.

This is the site of This is the site of transductiontransduction – the conversion of an electrical – the conversion of an electrical
signal into a chemical signal.signal into a chemical signal.

4. Neuromuscular Junction (NMJ)Neuromuscular Junction (NMJ)

5. Physiologic Anatomy of the Physiologic Anatomy of the
Neuromuscular JunctionNeuromuscular Junction
• Motor End Plate
• Synaptic trough/
gutter
• Presynaptic
terminal
• Postsynaptic
terminal
• Synaptic space/cleft
• Subneural cleft
• Acetylcholine (Ach)
• Synaptic vesicles
•
Acetylcholinesterase

6. The Neuromuscular junction consists ofThe Neuromuscular junction consists of
A/ Axon Terminal :A/ Axon Terminal : contains contains
around 300,000 vesicles whicharound 300,000 vesicles which
contain the neurotransmittercontain the neurotransmitter
acetylcholine (Ach).acetylcholine (Ach).
B/ Synaptic Cleft :B/ Synaptic Cleft :
20 – 30 nm ( nanometer ) space20 – 30 nm ( nanometer ) space
between the axon terminal & thebetween the axon terminal & the
muscle cell membrane. It containsmuscle cell membrane. It contains
the enzyme cholinesterase whichthe enzyme cholinesterase which
can destroy Achcan destroy Ach . .
C/ Synaptic Gutter ( Synaptic C/ Synaptic Gutter ( Synaptic
Trough)Trough)
It is the muscle cell membraneIt is the muscle cell membrane
which is in contact with thewhich is in contact with the
nerve terminal . It has many foldsnerve terminal . It has many folds
called called Subneural CleftsSubneural Clefts , which , which
greatly increase the surface area , greatly increase the surface area ,
allowing for accomodation of large allowing for accomodation of large
numbers of Ach receptors . Ach numbers of Ach receptors . Ach
receptors are located here . receptors are located here .

7. The Neuromuscular junction consists ofThe Neuromuscular junction consists of

The entire structure of axon The entire structure of axon
terminal , synaptic cleft and terminal , synaptic cleft and
synaptic gutter is called “ synaptic gutter is called “
Motor End-Plate ” .Motor End-Plate ” .

Ach is synthesized locally in Ach is synthesized locally in
the cytoplasm of the nerve the cytoplasm of the nerve
terminal , from active acetate terminal , from active acetate
(acetylcoenzyme A) and (acetylcoenzyme A) and
choline.choline.

Then it is rapidly absorbed Then it is rapidly absorbed
into the synaptic vesicles andinto the synaptic vesicles and
stored there. stored there.

The synaptic vesicles The synaptic vesicles
themselves are made by the themselves are made by the
Golgi Apparatus in the nerve Golgi Apparatus in the nerve
soma ( cell-body). soma ( cell-body).

Then they are carried by Then they are carried by
Axoplasmic Transport to the Axoplasmic Transport to the
nerve terminal , which nerve terminal , which
contains around 300,000 contains around 300,000
vesicles . vesicles .

8. Acetylcholine (1)Acetylcholine (1)

Ach is synthesized locally in Ach is synthesized locally in
the cytoplasm of the nerve the cytoplasm of the nerve
terminal , from active terminal , from active
acetate (acetylcoenzyme A) acetate (acetylcoenzyme A)
and choline.and choline.

Then it is rapidly absorbed Then it is rapidly absorbed
into the synaptic vesicles into the synaptic vesicles
andand
stored there. stored there.

The synaptic vesicles The synaptic vesicles
themselves are made by the themselves are made by the
Golgi Apparatus in the Golgi Apparatus in the
nerve soma ( cell-body). nerve soma ( cell-body).

Then they are carried by Then they are carried by
Axoplasmic Transport to the Axoplasmic Transport to the
nerve terminal , which nerve terminal , which
contains around 300,000 contains around 300,000
vesicles . vesicles .

Each vesicle is then filled Each vesicle is then filled
with around 10,000 Ach with around 10,000 Ach
molecules .molecules .

9. Acetylcholine (2)Acetylcholine (2)

When a nerve impulse When a nerve impulse
reaches the nerve reaches the nerve
terminal ,terminal ,

it opens calcium it opens calcium
channels channels 
calcium diffuses from calcium diffuses from
the ECF into the axon the ECF into the axon
terminal terminal  Ca++ Ca++
releases Ach from releases Ach from
vesicles by a process of vesicles by a process of
EXOCYTOSIS EXOCYTOSIS

One nerve impulseOne nerve impulse can can
release 125 Ach release 125 Ach
vesicles.vesicles.

The quantity of Ach The quantity of Ach
released by one nerve released by one nerve
impulse is more than impulse is more than
enough to produce one enough to produce one
End-Plate Potential .End-Plate Potential .

10. 
Ach combines with its Ach combines with its
receptors in the receptors in the
subneural clefts. This subneural clefts. This
opens sodium channels opens sodium channels
 & sodium diffuses into & sodium diffuses into
the muscle causing the muscle causing a a
locallocal,,non-propagated non-propagated
potential called the “ potential called the “ End-End-
Plate Potential (EPP)”,Plate Potential (EPP)”,. .

This EPP triggers a This EPP triggers a
muscle APmuscle AP which spreads which spreads
down inside the muscle down inside the muscle
to make it contract .to make it contract .

11. After ACh acts on the receptors , it is hydrolyzed by After ACh acts on the receptors , it is hydrolyzed by
the enzyme Acetylcholinesterase (cholinesterase ) the enzyme Acetylcholinesterase (cholinesterase )
into Acetate & Choline . The Choline is actively into Acetate & Choline . The Choline is actively
reabsorbed into the nerve terminal to be used again reabsorbed into the nerve terminal to be used again
to form ACh. This whole process of Ach release, to form ACh. This whole process of Ach release,
action & destruction takes about 5-10 ms . action & destruction takes about 5-10 ms .

12. 1425 – 20041425 – 2004
Destruction of AchDestruction of Ach

22. Clinical features

33. Drugs That Drugs That StimulateStimulate the Muscle Fiber by Ach-Like Action:the Muscle Fiber by Ach-Like Action:


Methacholine, Carbachol, and Nicotine.Methacholine, Carbachol, and Nicotine.
They act for minutes or hours—are not destructed by They act for minutes or hours—are not destructed by cholinesterase.cholinesterase.
Drugs That Drugs That StimulateStimulate the NMJ by Inactivating the NMJ by Inactivating
Acetylcholinesterase:Acetylcholinesterase:

Neostigmine, Physostigmine Neostigmine, Physostigmine [[inactivate inactivate acetylcholinesterase acetylcholinesterase for for
several hoursseveral hours]]

Diisopropyl fluorophosphate Diisopropyl fluorophosphate (nerve gas poison) (nerve gas poison) [inactivates [inactivates
acetylcholinesteraseacetylcholinesterase for weeks for weeks -------can cause death because of -------can cause death because of
respiratory muscle spasm]respiratory muscle spasm]
Drugs That Enhance or Block
Transmission at the
Neuromuscular Junction

34. Drugs That Drugs That BlockBlock Transmission at the NMJTransmission at the NMJ

Curare & Curariform like-drugs. Curare & Curariform like-drugs.
Prevent passage of impulses from the nerve ending into Prevent passage of impulses from the nerve ending into
the muscle by the muscle by blocking the action of Ach on its receptorsblocking the action of Ach on its receptors..
act by competitive inhibition to Ach at its act by competitive inhibition to Ach at its
receptors & can not cause Depolarization.receptors & can not cause Depolarization.

Botulinum ToxinBotulinum Toxin. .
Bacterial poison that Bacterial poison that decreases the quantity of Ach decreases the quantity of Ach
releaserelease by the nerve terminals. by the nerve terminals.
Drugs That Enhance or Block
Transmission at the
Neuromuscular Junction

35. Myasthenia GravisMyasthenia Gravis

Auto-immune disease Auto-immune disease

Antibodies against Ach receptors destroy many of the Antibodies against Ach receptors destroy many of the
receptors receptors  decreasing the EPP , or even preventing its decreasing the EPP , or even preventing its
formation formation  weakness or paralysis of muscles weakness or paralysis of muscles
( depending on the severity of the disease ) .( depending on the severity of the disease ) .

 patient may die because of paralysis of respiratory patient may die because of paralysis of respiratory
muscles. muscles.

TreatmentTreatment : Anti-cholinestersae drugs . These drugs : Anti-cholinestersae drugs . These drugs
inactivate the cholinesterase enzyme ( which destroys inactivate the cholinesterase enzyme ( which destroys
Ach) and thereby allow relatively large amounts of Ach Ach) and thereby allow relatively large amounts of Ach
to accumulate and act on the remaining healthy to accumulate and act on the remaining healthy
receptors receptors  good EPP is formed good EPP is formed  muscle contraction . muscle contraction .

36. 
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