NEUROMUSCULAR JUNCTION

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NEUROMUSCULAR JUNCTION

• Dr. Sidra Hamid
• Physiology Department

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CASE 4 35 year old woman with progressive muscle
weakness

• A 35 years old woman resident of Rawalpindi
  presented in foundation OPD with progressive
  weakness for the last 2 months. She has also
  noticed intermittent drooping of both of her eye
  lids, and progressive facial muscles weakness
  while speaking. She also complaints of weakness
  and tiredness while climbing the stairs of her
  office has difficulty while typing a lengthy
  official replies to their clients.

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• Her general physical examination revealed a pulse
  of 82/min. B.P 120/80 mm of Hg. Temp. 98 F and
  Resp. rate 16/min. with drooping of both eyelids
  ( Ptosis ive). Her laboratory investigations
  revealed positive anti-choline receptor
  antibodies. Rest of laboratory workup was
  unremarkable.

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LEARNING OBJECTIVES
Describe the physiological anatomy of
Neuromuscular Junction (NMJ). Terminal
button. Motor end plate. Motor End Plate
potential and how action potential is generated
in muscle. Synaptic trough/ gutter/
cleft. Chemicals/ drugs/ diseases effecting
neuromuscular transmission
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• ANIMATION

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DEFINITION

• The place where the motor neuron makes a
  functional contact with the skeletal muscle cell
  is called NEUROMUSCULAR JUNCTION or MYONEURAL
  JUNCTION

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Neuromuscular Junction

• Neuromuscular Junction
• A neuromuscular junction exists between a
  motor neuron and a skeletal muscle.
• - Synapse
• A junction between two neurons

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INNERVATION OF SKELETAL MUSCLE FIBERS

• Large, myelinated nerve fibers
• Originate from large motor neurons in the
  anterior horns of the spinal cord
• Each nerve fiber, branches and stimulates from
  three to several hundred skeletal muscle fibers
• The action potential initiated in the muscle
  fiber by the nerve signal travels in both
  directions toward the muscle fiber ends

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How myelinated fiber becomes unmyelinated
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MOTOR END PLATE

• The nerve fiber forms a complex of branching
  nerve terminals that invaginate into the surface
  of the muscle fiber but lie outside the muscle
  fiber plasma membrane
• Entire structure - motor endplate.
• Covered by one or more Schwann cells that
  insulate it from the surrounding fluids.

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AXON TERMINAL

• SYNAPTIC VESICLES
• Size 40 nanometers
• Formed by the Golgi apparatus in the cell body
  of the motor neuron in the spinal cord.
• Transported by axoplasm to the neuromuscular
  junction at the tips of the peripheral nerve
  fibers.
• About 300,000 of these small vesicles collect in
  the nerve terminals of a single skeletal muscle
  end plate.

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• MITOCHONDRIA
• Numerous
• Supply ATP
• Energy source for synthesis of excitatory
  neurotransmitter, acetylcholine
• DENSE BARS
• Present on the inside surface of neural
• membrane

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• VOL TAGE GATED CALCIUM CHANNELS
• Protein particles that penetrate the neural
  membrane on each side 0f dense bar
• When an action potential spreads over the
  terminal, these channels open and calcium ions
  diffuse to the interior of the nerve terminal.
• The calcium ions, exert an attractive influence
  on the acetylcholine vesicles, drawing them to
  the neural membrane adjacent to the dense bars.

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• The vesicles then fuse with the neural membrane
  and empty their acetylcholine into the synaptic
  space by the process of exocytosis
• Calcium acts as an effective stimulus for causing
  acetylcholine release from the vesicles
• Acetylcholine is then emptied through the neural
  membrane adjacent to the dense bars and binds
  with acetylcholine receptors in the muscle fiber
  membrane

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MUSCLE FIBER MEMBRANE

• SYNAPTIC TROUGH
• The muscle fiber membrane where it is invaginated
  by a nerve terminal and a depression is formed
• SYNAPTIC CLEFT
• The space between the nerve terminal and the
  fiber membrane is called the synaptic space or
  synaptic cleft

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• SUBNEURAL CLEFT
• Numerous smaller folds of the muscle membrane at
  the bottom of the gutter
• Greatly increase the surface area.
• ACETYLCHOLINE RECEPTORS
• Acetylcholine-gated ion channels
• Located almost entirely near the mouths of the
  sub neural clefts lying immediately below the
  dense bar areas

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ACETYLCHOLINE RECEPTORS

• Acetylcholine-gated ion channels
• Molecular weight -275,000

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• SUBUNITS
• Two alpha, one each of beta, delta, and gamma
• Penetrate all the way through the membrane
• Lie side by side in a circle- form a tubular
  channel
• Two acetylcholine molecules attach to the two
  alpha subunits, opens the channel
• RESTING STATE
• 2 Ach molecules not attached to the alpha subunit
  
• Channel remains constricted

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• OPENED Ach CHANNEL
• 2 Ach molecules attached to the alpha subunit of
  receptor
• Diameter- 0.65 nanometer
• Allows important positive ionsSODIUM, potassium,
  and calcium to move easily through the opening.
• Disallows negative ions, such as chloride to
  pass through because of strong negative charges
  in the mouth of the channel that repel these
  negative ions.

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• SODIUM IONS
• Far more sodium ions flow through the
  acetylcholine channels to the inside than any
  other ions
• The very negative potential on the inside of the
  muscle membrane, 80 to 90 mili volts, pulls the
  positively charged sodium ions to the inside of
  the fiber
• Simultaneously prevents efflux of the positively
  charged potassium ions when they attempt to pass
  outward

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• END PLATE POTENTIAL
• Opening the acetylcholine-gated channels allows
  large numbers of sodium ions to pour to the
  inside of the fiber
• Sodium ions carry with them large numbers of
  positive charges
• Creates a local positive potential change inside
  the muscle fiber membrane, called the end plate
  potential.
• End plate potential initiates an action potential
  that spreads along the muscle membrane
• Causes muscle contraction

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Events of Neuromuscular Junction

• Propagation of an action potential to a terminal
  button of motor neuron.
• Opening of voltage-gated Ca2 channels.
• Entry of Calcium into the terminal button.
• Release of acetylcholine (by exocytosis).
• Diffusion of Ach across the space.
• Binding of Ach to a receptor on motor end plate.

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Examples of Chemical Agents and Diseases that
Affect the Neuromuscular Junction

• Mechanism Chemical Agent or Disease
• Alters Release of Acetylcholine
• Cases explosive release of acetylcholine
  Black widow spider venom
• Blocks release of acetylcholine
  Clostridium botulinum toxin
• Block acetylcholine Receptor
• Bind reversibly Curare
• Auto antibodies inactivate acetylcholine
  Myasthenia gravis
• receptors
• Prevents inactivation of acetylcholine
• Irreversibly inhibits acetylcholinesterase
  Organophosphates
• Temporary inhibits acetylcholinesterase
  Neostigmine

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THANKS