Transcript 07-MN_Neuromuscular Junction.ppt

The Neuromuscular Junction
( Neuromuscular Synapse )
Dr. Taha Sadig Ahmed
Anterior •
Horn Cells
( Motor
Neurons ).
Motor Unit •
: is the
motor
neuron
(Anterior
horn Cell)
and all the
muscle
fibers it
supplies
Neuromuscular Junction (NMJ)
The Neuromuscular junction consists of
A/ Axon Terminal : contains
around 300,000 vesicles which
contain the neurotransmitter
acetylcholine (Ach).
B/ Synaptic Cleft :
20 – 30 nm ( nanometer ) space
between the axon terminal & the
muscle cell membrane. It contains
the enzyme cholinesterase which
can destroy Ach .
C/ Synaptic Gutter ( Synaptic
Trough)
It is the muscle cell membrane
which is in contact with the
nerve terminal . It has many folds
called Subneural Clefts , which
greatly increase the surface area ,
allowing for accomodation of large
numbers of Ach receptors . Ach
receptors are located here .
The Neuromuscular junction consists of





The entire structure of axon
terminal , synaptic cleft and
synaptic gutter is called “ Motor
End-Plate ” .
Ach is synthesized locally in the
cytoplasm of the nerve terminal
, from active acetate
(acetylcoenzyme A) and
choline.
Then it is rapidly absorbed into
the synaptic vesicles and
stored there.
The synaptic vesicles
themselves are made by the
Golgi Apparatus in the nerve
soma ( cell-body).
Then they are carried by
Axoplasmic Transport to the
nerve terminal , which contains
around 300,000 vesicles .
Acetylcholine (1)
 Ach is synthesized locally in
the cytoplasm of the nerve
terminal , from active acetate
(acetylcoenzyme A) and
choline.
 Then it is rapidly absorbed
into the synaptic vesicles and
stored there.
 The synaptic vesicles
themselves are made by the
Golgi Apparatus in the nerve
soma ( cell-body).
 Then they are carried by
Axoplasmic Transport to the
nerve terminal , which
contains around 300,000
vesicles .
 Each vesicle is then filled
with around 10,000 Ach
molecules .
Acetylcholine (2)
• When a nerve impulse
reaches the nerve
terminal ,
• it opens calcium
channels 
calcium diffuses from
the ECF int the axon
terminal  Ca++
releases Ach from
vesicles by a process of
EXOCYTOSIS
• One nerve impulse can
release 125 Ach
vesicles.
• The quantity of Ach
released by one nerve
impulse is more than
enough to produce one
End-Plate Potential .
 Ach combines with its
receptors in the subneural
clefts. This opens sodium
channels  & sodium
diffuses into the muscle
causing a local,nonpropagated potential
called the “ End-Plate
Potential (EPP)”, whose
value is 50 – 75 mV.
 This EPP triggers a
muscle AP which
spreads down inside the
muscle to make it cntract .
• After ACh acts on the receptors , it is hydrolyzed by the
enzyme Acetylcholinesterase (cholinesterase ) into
Acetate & Choline . The Choline is actively reabsorbed
into the nerve terminal to be used again to form ACh.
This whole process of Ach release, action & destruction
takes about 5-10 ms .
Myasthenia Gravis
• Auto-immune disease
• Antibodies against Ach receptors destroy many of the
receptors  decreasing the EPP , or even preventing its
formation  weakness or paralysis of muscles
( depending on the severity of the disease ) .
•  patient may die because of paralysis of respiratory
muscles.
• Treatment : Anti-cholinestersae drugs . These drugs
inactivate the cholinesterase enzyme ( which destroys
Ach) and thereby allow relatively large amounts of Ach to
accumulate and act on the remaining healthy receptors
 good EPP is formed  muscle contraction .
Drugs Acting on the NMJ
• Drugs that stimulate the muscle cell by Acetylcholine-like
action : nicotine , methacholine , carbachol .
• Drugs that block neuromuscular transmission : Curare and
curare-like drugs ( curariform drugs ) . They have a
chemical structure similar to ACh , but can not stimulate the
receptors . They occupy acetylcholine receptors and
thereby prevent ACh from acting on its receptors  muscle
weakness or paralysis . Example : Tubocurarine. It is used
during some surgical operations .
• Anticholinesterase drugs ( e.g. Neostigmine,Physostigmine)
Used in treatment of Myasthenia Gravis . These drugs
inactivate the cholinesterase enzyme ( which destroys Ach)
and thereby allow relatively large amounts of Ach to
accumulate and act on the remaining healthy receptors 
good EPP is formed  muscle contraction .
Muscle Physiology
The Muscle Action Potential
• Muscle RMP = -90 mV ( same as in nerves ) .
• Duration of AP = 1-5 ms ( longer duration than
nerve AP , which is usually about 1 ms ) .
• CV = 3-5 m/s ( slower than big nerves ) .
Muscle Contraction
There are 4 important muscle proteins :
A/ two contractile proteins that slide upon
each other during contraction:
(1) Actin
(2) Myosin ,
B/ And two regulatory proteins :
(1) Troponin  excitatory to contraction
(2) Tropomyosin  inhibitory to contraction
• Each muscle cell (fiber) is 10 -80
micrometer long & is covered by a cellmembrane called Sarcolemma.
• Each cell contains between a few
hundreds to a few thousands Myofibrils.
• Each Myofibril contains 3000 Actin
filaments & 1500 Myosin filaments .
• Each myofibril is striated: consisting of
dark bands (called A-bands) and
light (I-bands).
Muscle Structure (2)
 A-bands consist mainly of
Myosin & Actin ; while
I-bands consist of Actin.
 The ends of Actin are
attached byZ-Discs(Z-lines ).
 The part of the Myofibril lying
between two Z-discs is called
Sarcomere . It is about 2
mcrometers .
 When contraction takes
place Actin & Myosin slide
upon each other , & the
distance between two z-discs
decreases : This is called
Sliding Filament Mechanism
Sliding Filament Mechanism: will be discussed later )
Actin Filament consists of Globular G-actin molecules that are attached
together to form a chain.
like a double helix‫ا‬Each two chains wind together
Two F-Actin strands
Groove between the 2 Factin strands
> Each G-Actin molecule has a binding site for Myosin head
( called actin active sites )
> These active sites are covered and hidden from the Myosin head by
the inhibitory protein Tropomyosin
> When Troponin is activated by Ca++ it will move the Tropomyosin
away from these sites and expose them for Myosin.
> then myosin immediately gets attached to them .
> when the myosin head attaches to actin it forms a “ cross-bridge”
The diagram of Guyton
Myosin (1)
Each Myosin molecule has (1) Head (2) Hinge (joint ) •
and ( 3 ) Tail ; and each myosin head contains an ATP
binding site as well as ATP-ase enzyme .
Myosin (2)
Each 200 myosin molecules aggregate to form a •
myosin filament , from the sides of which project
myosin heads in all directions .
The EPP at the motor •
end-plate triggers a
muscle AP
The muscle AP spreads •
down inside the muscle
through the Transverse
Tubules ( T-tubules )
to reach the Sarcoplasmic
Reticulum (SR) .
In the SR the muscle AP 
opens calcium channels
( in the walls of the SR) 
calcium passively flows
out ( by concentration
gradient ) of the SR into
muscle cytoplasm
Ca++ combines with
Troponin
The activated troponin pulls the inhibitory protein 
tropomyosin away from the myosin binding sites on
actin
 and once these sites on Actin are exposed 
myosin heads quickly bind to them
This binding activates the enzyme ATPase in the Myosin
Head  it breaks down ATP releasing energy  which is
used in the “Power Stroke ” to move the myosin head
The “ power stroke ” means tilting of the cross-bridge head (
myosin head ) and dragging ( pulling ) of actin filament
• Then , on order to release the head of Myosin
from Actin , a new ATP is needed to come and
combine with the head of Myosin .
• Q: What is Rigor Mortis ?
• Q: ATP is neede for 3 things : what are they ?
• Q: Is muscle relaxation a passive or active
process ? Why ?
• Q: What happens to A-band and I-band during
contraction ?
• Q: Ca++ is needed in nerve & muscle : when
and where ?
Summary (1)
(1) Muscle AP spreads through T-tubules
(2) it reaches the sarcoplasmic reticulum where  opens
its Ca++ channels  calcium diffuses out of the
sarcoplasmic reticulum into the cytoplasm  increased
Ca++ concentration in the myofibrillar fluid .
(3) Ca++ combines with Troponin , activating it
(4) Troponin pulls away Tropomyosin
(5) This uncovers the active sites in Actin for Myosin
(6) Myosin combines with these sites
(7) This causes breakdown of ATP and release of snergy
which will be used in Power Stroke
(8) Myosin and Actin slide upon each other  contraction
(9) A new ATP comes and combines with the Myosin head
.This causes detachment of Myosin from Actin .
Summary (2)
• ATP is needed for 3 things :
• (1) Power stroke .
• (2) Detachment of myosin from actin
active sites .
• (3) Pumping C++ back into the
Sarcoplasmic reticulum .
Cardiac Muscle (1)
• Cardiac muscle is a type of highly oxidative (using
molecular oxygen to generate energy ) involuntary
striated muscle found in the walls of the heart,
• Cardiac muscle is adapted to be highly resistant to
fatigue: it has a large number of mitochondria,
enabling continuous aerobic respiration via oxidative
phosphorylation,
• Role of calcium in contraction
• In contrast to skeletal muscle, cardiac muscle
requires both extracellular calcium and sodium ions
for contraction to occur.
•
Cardiac Muscle (2)
• Like skeletal muscle, the depolarization phase
of the ventricular muscle action potential is
due to entry of sodium ions across into the
cell .
• However, an inward flux ( influx ) of
extracellular calcium ions through calcium
channels sustains the depolarization of
cardiac muscle cells for a longer duration ,
resulting in a “ plateau Phase ” that is not
present in the case of the skeletal muscle AP
• Therefore , the cardiac muscle AP lasts for a
long period ( 200-2300 ms ) and covers most
of the contraction phase . That is why cardiac
muscle can not be tetanized .
• Repolarization in the AP , like skeletal muscle ,
is due to potassium efflux .
Phases of the Cardiac Muscle AP (1)
• Phase 4
• Phase 4 is the Resting
Membrane Potential .
• The normal resting membrane
potential in the ventricular
myocardium is about -85 to -95
mV.
• This is the period that the cell
remains in until it is stimulated
by an external electrical
stimulus (typically an adjacent
cell).
• This phase of the action
potential is associated with
diastole ( relaxation ) of the
chamber of the heart
Phases of the Cardiac Muscle AP (2)
• Phase 0:
• Phase 0 is the rapid
depolarization
• Phase 1:
• Phase 1 of the action
potential occurs with
the inactivation of the
sodium channels .
Phases of the Cardiac Muscle AP (3)
• Phase 2
• Phase 2 is the "plateau"
phase of the cardiac AP
and is due to calcium
influx into the cell .
• Phase 3
• Phase 3 is the
repolarization phase and
is due to potassium efflux
•
•
•
•
Draw the relationship
between a cardiac AP
and cardiac muscle
contraction. How does
this situation compare
to excitation
contraction coupling of
skeletal muscle?
In skeletal muscle, the
electrical event is over
before the contraction
begins,
but in cardiac muscle,
the electrical and
mechanical events
overlap considerably.
Tetany is not possible
in cardiac muscle
because of the
prolonged refractory
period.