010 the neuromuscular junction Flashcards
describe the foetal/early formation of the neuromuscular junction
- 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
what happens to the ACh receptors as the neuromuscular junction forms?
- 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
how does the ACh receptor change structure from embryonic to adult?
- 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
how do neural innervation/connections change from foetus to birth?
- when fetus develops it creates too many neural connections (backups) which gradually degenerate from birth onwards and the innervation is more focused
describe what a single motor unit is
- 1 nerve from the spinal cord with many terminals, innervating many muscle fibres
how does motor unit size determine the precision of movement?
- 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
describe the overall broad structure of the neuromuscular junction
- cell body of motorneuron —> myelinated axon —> terminal branches of axon —> motor end plate —> nerve terminal surrounded by Schwann cells at sarcolemma of muscle
describe in detail the structure/features of the presynaptic nerve terminal at the neuromuscular junction
- 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
describe the vesicle cycle in the presynaptic nerve terminal
- 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
describe what the quantal release of neurotransmitters at the nmj is
- 1 quantum generates a miniature end plate potential, which is the smallest amount of stimulation 1 neuron can send to another neuron
what is the membrane potential of muscle?
- 90mV
describe the structure of the muscle at the neuromuscular junction
- 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
describe how a contraction occurs in muscle from an action potential in a motor neuron
- 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
describe the relationship with ATP and myosin cross-bridges
- 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.
what type of effect does the motor neuron have on muscle?
trophic effect, controlling gene expression
describe what happens to the muscle fibres after a single nerve stimulus and what the graph would look like
- single muscle twitch
- 1 peak and then plateau if no more stimulation
describe what happens to the muscle fibres after 2 stimuli, 100ms apart, 10Hz and what the graph looks like
- pair of muscle twitches
- 2 peaks combined, second is larger
describe what happens to the muscle fibres after 5 stimuli, 40ms apart, 25Hz
- partially fused tetanus
- 5 peaks all joined (small, narrow individual peaks)
- muscle tremors
describe what happens to the muscle fibres after constant stimuli of 100Hz
- tetanus
- 1 big long peak
- bigger and stronger contraction
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)
where on a force/power and velocity of shortening graph is the isometric contraction?
- isometric contraction = y axis intercept = highest force, when velocity =0
where on a force/power and velocity of shortening graph is the isotonic contraction?
- when force = 0 and shortening velocity is at highest
how much of the maximum muscle shortening velocity is there when maximum power is reached?
- 1/3 of maximum velocity
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
what is used to block the neuromuscular junction?
- atracurium = competes with ACh receptor, used in surgery/intubation
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
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
