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Dr.

Hoe See Ziau


Department of Physiology
Faculty of Medicine
University of Malaya
Types of Connection
 Connection with another neuron
→ a synapse
 Connection with muscle (skeletal, cardiac
or smooth)
→ a neuromuscular junction (NMJ)
Neuromuscular Junction (NMJ)
 Special junction between a
axon terminal and a muscle
fibre
 Axon terminal is enlarged into
a knob-like structure →
terminal button (Synaptic knob)
Structure of NMJ
 Located in the middle of
the long cylindrical muscle
fibre
 No myelin sheath
 Lots of mitochondria and
vesicles
 No direct contact between
axon and muscle
 Synaptic cleft – 50-100nm
(narrow space)
Structure of NMJ
 Motor End Plate (MEP)
– differentiated version
of membrane of muscle
fibre
 MEP – numerous
junctional folds
 To increase surface area

 ACh Receptors
Neurotransmitter at NMJ
 Occurs chemically – a chemical messenger
is used to carry the signal between the
neuron terminal & the muscle fiber
 Synaptic knobs – 200 000 to 300 000
vesicles
 Contain neurotransmitter: acetylcholine
(ACh)
 ACh binds with nicotinic cholinergic receptor
at the post-synaptic membrane
 Small amount of ACh that does not bind will
be loss
Neurotransmitter at NMJ
 After binding with the receptor (1
– 2 msec after released), ACh will
be hydrolysed to choline and
acetate by acetylcholinesterase
 Choline returns to motor nerve
terminal for ACh resynthesis
 ACh recycled
Quantal Release of ACh
1. The presence of an action potential in
the terminal button triggers the
opening of voltage-gated Ca2+
channels
→ Influx of Ca2+ into the terminal button

2. Ca2+
→ triggers the vesicles to dock onto
terminal membrane
→ Also causes docked vesicles to fuse
with the membrane and the release of
Ach into synaptic cleft by exocytosis

 1 vesicle = 1 quantum (contains ~


10,000 ACh)
 Each nerve impulse can stimulate the
release of 100 quanta ( 106 ACh)
End-Plate Potential (EPP)
 Depolarisation of motor end plate
 Graded potential
 Magnitude depends on the amount and duration of ACh at
the end-plate
 Undergoes summation
 When the EPP reaches threshold ( -50 mV)
→ Action potential in adjacent muscle membrane
Formation of the EPP
 ACh diffuses to the motor end-plate
 ACh binds to specific receptor site on
motor end-plate
 Binding of ACh with receptor
→ chemical-gated channels to opens
→ non-specific: influx of Na+ and efflux of K+
→ Influx of Na+ > efflux of K+
→ local depolarisation of membrane → End-
plate potential
→ ↑ binding → ↑ EPPs
End-Plate Potential (EPP)
 The motor end plate region does not have a threshold
potential, so an action potential cannot be initiated at this site
 EPP brings about an action potential in the rest of the adjacent
muscle fibres
 When EPP takes place, local current flow occurs between the
depolarised end plate & the adjacent, resting cell membrane in
both direction, opening voltage-gated Na+ channels →
reducing the potential to threshold in the adjacent areas →
action potential
 Action potential spreads to whole skeletal muscle
Miniature End-Plate Potential (MEPP)
 At rest → random movements of vesicles (Brownian
movements)
 When one vesicle touches terminal membrane →
spontaneous release one quantum of ACh by
exocytosis
 At motor end-plate → causes small depolarisation of
membrane
 Small depolarisations are called miniature EPPs
 Not followed by an action potential
Events at an NMJ
1. An action potential in a motor
neuron is propagated to the
terminal button
2. The presence of an action
potential in the terminal button
triggers the opening of voltage-
gated Ca2+ channels and the
subsequent entry of Ca2+ into
the terminal button
3. Ca2+ triggers the release of ACh
into synaptic cleft by exocytosis
Events at an NMJ
4. ACh diffuses across the synaptic cleft &
binds with ACh receptors on the motor end
plate of the muscle cell membrane

5. This binding brings about the opening of


cation channels, leading to a relatively
large movement of Na+ into the muscle cell
compared to a smaller movement of K+
outward

6. The result is an end-plate potential (EPP).


Local current flow occurs between the
depolarised end plate & adjacent
membrane

7. This local current flow opens voltage-gated


Na+ channels in the adjacent membrane
Events at an NMJ
8. The resultant Na+ entry
reduces the potential to
threshold, initiating an action
potential, which is propagated
throughout the muscle fibre
 Muscle action potential spreads
through the T tubules
→ causes Ca2+ to be released from
sarcoplasmic reticulum
→ Ca2+ binds with troponin C, actin
slides into myosin
→ Contraction
Events at an NMJ
9. ACh hydrolysed to choline +
acetate and taken back into
presynaptic knob
 Motor end-plate repolarises
 inside the presynaptic knob,
choline + acetyl CoA recombine
and taken back into vesicles
Events at an NMJ

8 8
Na+ 7

9
Neuromuscular Fatigue
 25 quanta of ACh are needed to generate muscle
action potential
 If the nerve that supplies the muscle is stimulated
>100 times/second,
→ rate of ACh released >> rate of ACh resynthesis
→ no impulse transmission across NMJ
→ no contraction
 Known as neuromuscular fatigue
Dysfunction at NMJ
 Myasthenia gravis
 Autoimmune disease

 Body produces antibodies against


own motor end-plate ACh
receptors
 Decrease EPPs produced

 Condition characterised by
extreme muscular weakness
 Treat with anticholinesterase (e.g.:
neostigmine or physostigmine)
→To decrease the activity of
acetylcholinesterase
Substances Affecting the NMJ
Substances Mechanism
Alter release of ACh
• Black widow spider venom • Causes explosive release of ACh
• Clostridium botulinum toxin • Blocks release of ACh
Block ACh receptor sites
• Curare • Reversibly binds with Ach receptor
sites
Prevents inactivation of ACh
• Organophosphates (certain • Irreversibly inhibits
pesticides and military gas) acetylcholinesterase (AChE)
• Neostigmine (for treatment of • Temporarily inhibits AChE
myasthenia gravis)
Substances Affecting the NMJ
Botulinum Toxin
 Powerful toxin produced by
Clostridium botulinum
 Responsible for deadly food
poisoning – botulism
 Now use for some specific
movement disorders
 Also now used for fighting
wrinkles by cosmetic surgeons
 Marketed as “Botox” –
therapeutic doses remove
wrinkles (facial rejuvenation)
Differences Between EPP and Action Potential
EPP Action Potential
• Local events, not propagated • Propagated
• No threshold • Has threshold
• No refractory period • Refractory period – absolute and
relative

• Can summate • Cannot summate – all-or-none law


• Graded response • Not graded – amplitude constant
• Initiated by neurotransmitter (Ach) • Initiated by membrane
depolarisation

• Dominated by chemical-gated • Dominated by voltage-gated


channels channels