The%20Neuromuscular%20Junction%20(%20Neuromuscular%20Synapse%20)

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The Neuromuscular Junction( Neuromuscular
Synapse )

• Dr. Taha Sadig Ahmed

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• Anterior Horn Cells ( Motor Neurons ).

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• Motor Unit is the motor neuron (Anterior horn
  Cell) and all the muscle fibers it supplies

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Neuromuscular Junction (NMJ)
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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 .

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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 .

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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 .

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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 .

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• Ach combines with its receptors in the subneural
  clefts. This opens sodium channels ? sodium
  diffuses into the muscle causing a
  local,non-propagated 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 .

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• 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 .

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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 .

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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 .

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Muscle Physiology
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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 ) .

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Muscle Contraction

• There are 4 important muscle proteins
• A/ two contractile proteins that slide upon each
  other during contraction
• Actin
• Myosin ,
• B/ And two regulatory proteins
• Troponin ? excitatory to contraction
• Tropomyosin ? inhibitory to contraction

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• Each muscle cell (fiber) is 10 -80 micrometer
  long is covered by a cell-membrane 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).

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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

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Sliding Filament Mechanism will be discussed
later )
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Actin Filament consists of Globular G-actin
molecules that are attached together to form a
chain. Each two chains wind together?like a
double helix
Two F-Actin strands
Groove between the 2 F-actin strands
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gt Each G-Actin molecule has a binding site for
Myosin head( called actin active sites ) gt
These active sites are covered and hidden from
the Myosin head by the inhibitory protein
Tropomyosin gt When Troponin is activated by Ca
it will move the Tropomyosin away from these
sites and expose them for Myosin.gt then myosin
immediately gets attached to them .gt when the
myosin head attaches to actin it forms a
cross-bridge
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The diagram of Guyton
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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 .

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Myosin (2)

• Each 200 myosin molecules aggregate to form a
  myosin filament , from the sides of which project
  myosin heads in all directions .

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• 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

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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
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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
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The power stroke means tilting of the
cross-bridge head ( myosin head ) and dragging (
pulling ) of actin filament
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• 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 ?

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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 .

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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 .

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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.

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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 .

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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

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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 .

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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

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• 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.