[010] The Neuromuscular Junction Flashcards
What are the steps involved in the formation of the neuromuscular junction?
- Neural crest cells migrate and fuse to form myotubes (multinucleate)
- NCCs also form Schwann cells and grow towards myotubes
- Nerve terminals contact muscle fibres after the fusion of myoblasts to form myotubes
- Processes grow out of the neural tube which form motor axons
- There travel down the Schwann cell to form axon terminals where it contacts the muscle fibre
- As the junction between the muscle fibre and nerve ul matures, the neuromuscular junction forms
Why is clustering of AChRs important?
As it increases the sensitivity of the muscle fibre to ACh for the muscle to be effectively stimulated by the nervous system.
What does the sensitivity of muscle depend on?
The presence of ACh receptor on the muscle fibre membrane near the nerve terminal
How does the distribution of ACh receptors on the muscle fibre change before and after birth?
Before birth, the ACh receptors are initially widely distributed across the entire surface of the muscle fibre however after birth and muscle fibre innervation, the receptors become localised in expression to the region of muscle fibre that is in contact with the new terminal (with muscle fibres not being expressed elsewhere along the fibres length).
What is the process to control clustering of receptors at NMJ?
This process only occurs if the original NMJ is intact and undamaged.
Agrin is released from a nerve terminal and binds MuSK. This changes gene expression of nuclei under the nerve terminal and controls clustering of ACh receptors at the neuromuscular junction.
What else is Agrin-MuSK signalling involved in?
Basal - Lamina formation (related to muscle fibres to mechanically support the muscle fibre during active contraction)
What is the structure of ACh receptors in the embryo (in terms of subunits)?
In the embryo, there are 2 alpha subunits, beta subunit, gamma subunit and a delta subunit.
What happens to the structure of the ACh receptor following birth?
Following birth, the gamma submit switches to an epsilon subunit in adults
How many nerve terminals is initially connected to each muscle fibre?
3
Why are there multiple nerve contacts with each muscle fibre, before birth?
This is so if any of the nerve contacts fail, the others can take over
What happens to the number of nerve contacts per fibre after birth and why?
The number of contacts per fibre decreases due to competition between nerve terminals causing elimination of less functional nerve terminals.
Which muscle retains polyneural connections even after birth?
Extra-occular muscles
What are 2 functions of myelin (produced by Schwann Cells)?
- Insulates axon to increase conduction velocity via saltatory conduction
- Support the nerve - notably its regrowth into the muscle fibre when damaged.
What does the motor unit show and what does a high motor unit mean?
The motor unit determines the precision of movement, muscles with a higher motor unit have larger motor units.
What is the function of the post synaptic sarcolenmna (motor end plate)?
The motor end plate is where the AChRs are localised to.
How is an action potential created by ACh?
- There are folds in the motor end plate
- On these folds, ACh receptors cluster and are localised where they would be most sensitive to the released neurotransmitter.
- Active zones (where ACh is released from) are opposite the AChRs.
- Acetylcholinesterase is found close to ACh aggregates in the functional clefts of the motor end plates
- There are voltage dependant sodium channels at the base of the junctional clefts which initiate the action potential
What is the vesicle cycle?
- They are formed from intracellular membrane
- They are filled with ACh and collect in the active zone
- When an action potential arrives at the presynaptic membrane the reside fuses with the terminal membrane and ACh is released into the synaptic cleft
- This causes the [ACh] to increase rapidly
- Vesicles are then recaptured, refilled and reused again, continuing the cycle.
What is a quanta?
A quanta is a packaged vesicle in which neurotransmitter is released in synapses
What is a miniature end plate potential (mepp)?
It is how much 1 quanta can generate, the smallest amount of stimulation 1 neuron can send to another one.
What is the end plate potential (epp)?
The sum of many MEPP is the EPP. A normal EPP usually causes postsynaptic neurone to reach its threshold of excitation and elicit an action potential.
When is the only time that MEPPs are observed?
When nerve touches muscle. This means that when an electrode is placed away from the NMJ only the muscle action potential can be recorded and not MEPPs
What are the steps involved in the initiation of muscle contraction?
- ACh binds to AChRs, triggering an action potential in the sarcolemma
- The action potential is conducted down t tubules into the muscle fibre
- In the muscle fibre, the voltage change caused by the action potential is detected by the T tubule dihydropyridine receptor ( calcium channel) which directly connects to the sarcosplasmic reticulum
- The dihydropyridine receptor undergoes a conformational change and transmits this change to sarcoplasmic ryanodine receptor
- Calcium is released from the sarcoplasmic reticulum via the opened ryanodine receptors and onto the myofibrils - allowing rapid skeletal muscle contraction
What colour are fast twitch fibres?
White ( no myoglobin)
What is the colour of slow twitch muscle fibres?
Red (myoglobin)
Which fibres are used for aerobic activity and which fibres are parity anaerobic?
Slow fibres are aerobic endurance muscles and fast muscles are partly anaerobic
What proteins do slow twitch muscle fibres express?
Alpha- actinin ll and troponin I slow (Tnls)
What proteins do fast twitch muscle fibres express?
Alpha- actinin ll, alpha-actinin lll and troponin I fast (tnIf)
How is muscle contraction strength controlled by CNS?
As the strength of the contraction depends on the number of motor units activated and the synchrony of their activation, both of which the CNS control.
Why is there trembling in people with a large amount of adrenaline?
As stimulating beta-adrenoreteptors on muscle causes the twitch to be faster so contraction is less smooth resulting in trembling
What is a muscle twitch, pair of twitches, partially fused tetanus and tetanus?
A single nervous stimulus causes a twitch.
If the second stimulus occurs before the first muscle has relaxed the twitch and muscle is summated
If stimulation frequency increases to around 25 Hz this causes a partially fused tetanus (jerky)
If stimulation frequency increases to around 100 Hz this causes a larger increase in tension with each summation but this increase is smooth producing a fused tetanus
Why does force decrease as power increases?
Power = force x velocity
Forming Cross bridges takes time so when the speed of filaments sliding increases, force decreases as there is less time for Cross bridges to form and fewer form as a result
What is passive tension?
When muscle fibres themselves stretch beyond their resting length. With passive tension, tension increases as passive tension increases
What is active tension?
Extra tension generated as result of a stimulus. Here, active tension reaches its maximum when the muscle fibre is at its resting length
Why are tetanus contractions more easily blocked by NMJ blockers?
As NMJ blockers are frequency dependant and produce a more profound block as the frequency of nerve impulses increases e.g. Atracurium
Give an example of a neuromuscular junction blocker
Atracurium
How does atracurium work on ACh?
Atracurium works by blocking the ACh binding site on the AChRs of the motor end plate, preventing the generation of the EPP and the muscle AP subsequently
What is edrophonium?
It is an aceytycholinesterase inhibitor so reverses the neuromuscular block produced
What is the iceberg effect?
75% of ACh receptors need to be blocked before neuromuscular transmission begins to be blocked and muscle twitch decreases
Why is the Iceberg effect important?
As t means that there is a large margin of safety before transmission is blocked
At what percentage block does complete twitch block occur?
95%
Why is it important to give drugs to reverse NMJ blockers after giving a patient NMJ blockers?
As it is possible that up to 75% of AChRs are blocked even after they have recovered. Occasionally there can be a reappearance of NMJ blocker in a patient’s system which would cause them to exceed 75% blockage, causing EPP to decrease - this can paralyse respiratory muscles.
Give 3 clinical examples of muscle weakness.
- Myasthenia gravis: autoimmune loss of AChRs
- Neuromuscular block by blocking AChRs: poisoning by venous snake and their venom contains alpha toxins like alpha bungarotoxin - causes respiratory depression and can lead to asphyxiation due to paralysis of the diaphragm
- Nicotine insecticide poisoning: desensitisation of AChRs and depolarising the neuromuscular block
