Transcript NMJ-1

NEUROMUSCULAR JUNCTION
Dr. Sidra Hamid
Physiology Department
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.
• 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.
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
• ANIMATION
DEFINITION
“ The place where the motor neuron makes a
functional contact with the skeletal muscle cell is
called NEUROMUSCULAR JUNCTION or
MYONEURAL JUNCTION”
Neuromuscular Junction
- Neuromuscular Junction
A neuromuscular junction exists between a
motor neuron and a skeletal muscle.
- Synapse
A junction between two neurons
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
How myelinated fiber becomes
unmyelinated
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.
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.
• MITOCHONDRIA
▫ Numerous
▫ Supply ATP
▫ Energy source for synthesis of excitatory
neurotransmitter, acetylcholine
• DENSE BARS
▫ Present on the inside surface of neural
membrane
• 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.
▫ 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
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
• 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
ACETYLCHOLINE RECEPTORS
• Acetylcholine-gated ion channels
• Molecular weight -275,000
• 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
• OPENED Ach CHANNEL
▫ 2 Ach molecules attached to the alpha subunit of
receptor
▫ Diameter- 0.65 nanometer
▫ Allows important positive ions—SODIUM,
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.
• 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
• 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
Events of Neuromuscular Junction
1.
2.
3.
4.
5.
6.
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.
Examples of Chemical Agents and Diseases
that Affect the Neuromuscular Junction
Mechanism
Disease
Alters Release of Acetylcholine
* Cases explosive release of acetylcholine
* Blocks release of acetylcholine
Chemical Agent or
* Black widow spider venom
* Clostridium botulinum toxin
Block acetylcholine Receptor
* Bind reversibly
* Auto antibodies inactivate acetylcholine
receptors
* Curare
* Myasthenia gravis
Prevents inactivation of acetylcholine
* Irreversibly inhibits acetylcholinesterase
* Temporary inhibits acetylcholinesterase
* Organophosphates
* Neostigmine
THANKS