010 the neuromuscular junction Flashcards
1
Q
describe the foetal/early formation of the neuromuscular junction
A
- neural crest cells beneath the ectoderm form myogenic precursors which forms muscle and Schwann cells
- Schwann cells have a growth cone at the bottom which binds to the myotube of muscle
- a synaptic bouton forms at the connection of muscle and nerve cell
- eventually develops further and forms neuromuscular junction as terminal Schwann cell associates with the muscle
2
Q
what happens to the ACh receptors as the neuromuscular junction forms?
A
- muscle is expressing subunits for ACh receptors so it becomes more sensitive to ACh
- the motor neuron axons secrete protein agrin which binds to ACh receptors on the muscle, aggregating them together, strengthening them
- agrin also helps form the basement membrane/basal lamina
3
Q
how does the ACh receptor change structure from embryonic to adult?
A
- embryonic = alpha (2), Beta, delta, and gamma
- adult = alpha (2), Beta, delta, epsilon
- gamma —> epsilon
- nucleus at the neuromuscular junction express genes for the epsilon subunit for receptor at birth
4
Q
how do neural innervation/connections change from foetus to birth?
A
- when fetus develops it creates too many neural connections (backups) which gradually degenerate from birth onwards and the innervation is more focused
5
Q
describe what a single motor unit is
A
- 1 nerve from the spinal cord with many terminals, innervating many muscle fibres
6
Q
how does motor unit size determine the precision of movement?
A
- the larger the motor unit size, the less precise the muscle movements
- e.g. temporalis muscle in the head = motor unit size of 500, extra-occular eye muscle = motor unit size of 5
7
Q
describe the overall broad structure of the neuromuscular junction
A
- cell body of motorneuron —> myelinated axon —> terminal branches of axon —> motor end plate —> nerve terminal surrounded by Schwann cells at sarcolemma of muscle
8
Q
describe in detail the structure/features of the presynaptic nerve terminal at the neuromuscular junction
A
- Schwann cell surrounding nerve terminal (insulation)
- mitochondria and microtubules in nerve terminal
- acetylcholine in vesicles in nerve terminal
- voltage-gated calcium channels
- basement membrane in synaptic cleft
9
Q
describe the vesicle cycle in the presynaptic nerve terminal
A
- delivery of synaptic vesicle components to the membrane
- endocytosis of components to delivery to endosome
- synaptic vesicle buds off the endosome
- the vesicle is then loaded with ACh/neurotransmitters
- vesicle binds to membrane (docking) and exocytosis occurs, releasing ACh/neurotransmitter into the synaptic cleft
10
Q
describe what the quantal release of neurotransmitters at the nmj is
A
- 1 quantum generates a miniature end plate potential, which is the smallest amount of stimulation 1 neuron can send to another neuron
11
Q
what is the membrane potential of muscle?
A
- 90mV
12
Q
describe the structure of the muscle at the neuromuscular junction
A
- sarcolemma - membrane with ACh receptors
- T tubules in the sarcolemma going deep down into muscle
- Dihydropyridine receptors (DHPR) in the T-tubule activated by action potential
- DHPR linked to sarcoplasmic reticulum ryanodine (RYR1) receptor
- myofibrils with sarcomere units with myosin and actin
- SERCA(sarco/endoplasmic reticulum Ca/ATPase), Ca/ATPase pump on the sarcoplamsic reticulum membrane
13
Q
describe how a contraction occurs in muscle from an action potential in a motor neuron
A
- action potential from motor neuron triggers Na channels to open = depolarisation = Ca channels open and initiate ACh vesicle fusion = ACh release at nmj
- bind to AChR and Na ions flow through channel into muscle = Depolarising = generating endplate potential (epp)
- action potential travels down T-tubules of sarcolemma
- action potential triggers DHPR on T-tubules, which triggers RYR1 receptor on sarcoplasmic reticulum to open
- this releases Ca into sarcoplasm
- Ca then interacts with the myofibrils sarcomere units
- Ca binds to troponin, which alters tropomyosin and exposes myosin binding site on actin to form cross-bridges
- actin-myosin binding shortens the sarcomere-sliding filament mechanism, contracting the muscle
- after contraction, repolarisation of sarcolemma and T-tubules closes DHPR and RYR1 and the SERCA pump on the sarcoplasmic reticulum pumps Ca back in, so muscle relaxes
14
Q
describe the relationship with ATP and myosin cross-bridges
A
- ATP hydrolysis into ADP and P causes myosin head to move forward
- the myosin head detaches ADP and binds to actin
- myosin moves backwards to original moving actin strand with it (shortening sarcomere)
- myosin head binds to ATP, detaching from actin then repeat from 1.
15
Q
what type of effect does the motor neuron have on muscle?
A
trophic effect, controlling gene expression
16
Q
what muscle fibre types are most muscles?
A
- a mixtured of type 1 (red) and type 2 (white)
17
Q
what is the muscle fibre type determined by?
A
- by the expression of the contractile proteins, troponin 1, determined by motor neuron activity
18
Q
what proteins does type 1/slow muscle fibre express?
A
- alpha-actinin-2 and troponin 1 slow (TnIs)
19
Q
what proteins does type 2/fast muscle fibre express?
A
- alpha-actinin-2 and 3 and troponin 1 fast (TnIf)
20
Q
what is an individual muscle fibre contraction called?
A
twitch
21
Q
describe what happens to the muscle fibres after a single nerve stimulus and what the graph would look like
A
- single muscle twitch
- 1 peak and then plateau if no more stimulation
22
Q
describe what happens to the muscle fibres after 2 stimuli, 100ms apart, 10Hz and what the graph looks like
A
- pair of muscle twitches
- 2 peaks combined, second is larger
23
Q
describe what happens to the muscle fibres after 5 stimuli, 40ms apart, 25Hz
A
- partially fused tetanus
- 5 peaks all joined (small, narrow individual peaks)
- muscle tremors
24
Q
describe what happens to the muscle fibres after constant stimuli of 100Hz
A
- tetanus
- 1 big long peak
- bigger and stronger contraction
25
describe the force/power and velocity of shortening graph/relationship
- velocity of shortening increases, force decreases (downwards curve from y axis)
- velocity of shortening increases, power increases. then reaches a maximum, then falls back down (upwards hill curve)
26
where on a force/power and velocity of shortening graph is the isometric contraction?
- isometric contraction = y axis intercept = highest force, when velocity =0
27
where on a force/power and velocity of shortening graph is the isotonic contraction?
- when force = 0 and shortening velocity is at highest
28
how much of the maximum muscle shortening velocity is there when maximum power is reached?
- 1/3 of maximum velocity
29
describe the relationship of active/passive tension and change in muscle length
- tension on y axis
- change in muscle length on x axis
- active tension = extra tension generated as a result of a stimulus = tension increases as change is muscle length increases up to peak and then decreases = here active tension is reached when muscle fibre at resting length
- passive tension = when muscle fibres themselves stretch beyond their resting length = starts later on, tension increases quite a lot as change in muscle length increases, beyond active tension
30
what is used to block the neuromuscular junction?
- atracurium = competes with ACh receptor, used in surgery/intubation
31
what is used to reverse neuromuscular junction block?
- atropine (reverses AChR block) and edrophonium ( inhibits enzyme that breaks down ACh)
- always give after blockers as even after patient has recovered, the blockers can still be there and reappear later = paralyse breathing muscles
32
what is the margin of safety/ iceberg effect with nmj blockers?
- 75% of ACh receptors need to be blocked before the neuromuscular transmission starts being blocked, making it very reliable
- about 5x as much ACh is released from the nerve terminal as is needed ti just evoke a muscle fibre action potential
- complete twitch block occurs at 95% receptor block
33
give 3 clinical examples of muscle weakness
- myasthenia = autoimmune loss of AChR
- Neuromuscular block = poisoning by venomous snakes of the elapid species (e.g. sea snakes and cobras), the venom contains a-bungarotoxin (binds irreversibly to AChR)
- Nicotine insecticide poisoning = desensitisation of AChR and depolarising neuromuscular block
