Lecture 10 - Neuromuscular Flashcards
What structure passes a signal from a motor neurone to a muscle?
Neuromuscular junction
What stimulates the release of neurotransmitter into the synaptic cleft of the neuromuscular junction?
Ca2+
How does Ca2+ influx causing neurotransmitter release occur?
Depolarisation stimulates Voltage Gated Ca2+ Channels to open
What generally happens at the nerve terminal once action potential reaches it?
VG Ca2+ channels open
Ca2+ influx
Increased [Ca2+]
ACh (Neurotransmitter) released into synaptic cleft
How does an increased frequency in action potentials to a nerve terminal affect terminal Ca2+ influx and therefore neurotransmitter release?
Increased amount of Ca2+ influx
MORE Neurotransmitter released
What is the structure of a Voltage-gated Ca2+ channel similar to?
Voltage gated Na+ channel
What is the structure of a voltage gated Ca2+ channel?
1 alpha sub unit made up of 4 repeats
Charged amino acids on repeats I and IV
What is a common Ca2+ channel?
L Type voltages gated Ca2+ channels
What family of drugs are used to block L-Type Ca2+ channels?
DHP (Dihydropyridines)
E.g Nifedipine
What is the significance of other subunits associating with Na+ channels or Ca2+ channels?
Fine tunes the properties
Ensures it carries out set function
What can the post synaptic membrane of a neuromuscular junction be called?
End plate
What receptors are present of the end plate/post synaptic membrane at a neuromuscular junction?
nACHR (Nicotinic Aceytlcholine receptors)
Once Ca2+ influx to axon terminal at a neuromuscular junction has occured, what happens? How does the neurotransmitter get released into the cleft?
Ca2+ binds to synaptotagmin
Vesicle bought close to membrane
Snare complex make a fusion pore
Transmitter released through this pore
Where is synaptotagmin?
On vesicle membrane
Where is the snare complex?
On the presynaptic membrane
How many ACh need to bind to the nACHR on the skeletal muscle membrane?
2 to each nAChR
What is the selectivity of nicotinic Acetylcholine receptors like?
Not very specific
Allows cations to move through
Na+ and Ca2+ in
K+ out
What type of channel are nAChR?
Ligand gated ion channels
What happens when ACh binds to the AChR on the muscle membrane (end plate)?
Na+ influx into muscle causing depolarisation
If threshold potential reached Action potential in smooth muscle will be fired
What is the depolarisation that occurs before an action potential occurs in the end plate (muscle) at a neuromuscular junction?
End plate potential
How does amount of Ca2+ entry into axon terminal effect end plate potential?
Less Ca2+ in terminal = less neurotransmitter released = less nAChR opened = less Na+ into end plate = LOWER AMPLITUDE End plate potential
What is the problem with lower amplitude end plate potentials at a neuromuscular junction?
Unlikely to depolarise enough to reach threshold potential for an action potential
What is the enzyme that breaks down the ACh on the Na+ ligand gated ion channels (nAChR) on the end plate/postsynaptic membrane?
Aceytlcholine esterase
ACh esterase
What is the effect of blocking nicotinic ACh receptors at neuromuscular junctions?
Paralysis since action potentials cannot be fired due to prevention of depolarisation (no Na+ influx)
What are the 2 types of blockers of nACh receptors?
Competitive blockers
Non competitive blockers
What is an example of a competitive nAChR blocker?
d-tubocurarine (d-TC)
What is the mode of action of d-TC (d-tubocurarine)?
Competes with ACh for the binding site of the nAChR (Ligand gated Na+ channel)
What happens with the competitive blocker d-tubocurarine (d-TC) when ACh concentration is very high?
ACh may outcompete d-TC so its effects are minimal
How does the nAChR blocker succinylcholine work?
Activates nAChR maintaining depolarisation causing the nACh channels to inactivate
In surgery what is important to accompany a neuromuscular blocker and why?
Neuromuscular blocker = paralysis
Anaesthetic = to not feel pain
A patient who has only had a neuromuscular blocker wont be able to move but will be able to feel the pain
What is Mayasthenia gravis?
Autoimmune disease targeting nACh receptors
What effect does Mayasthenia gravis have on the end plate at a neuromuscular junction?
Damages the nAChR reducing number of functional channels
More ACh needed to reach threshold potential
What effect does Mayasthenia gravis have on muscles and why?
Profound weakness
Due to endplate potentials being reduced in amplitude
Means threshold potentials often not reached
How can Myasthenia gravis be diagnosed?
Inhibit the ACh esterase enzyme so the ACh is not quickly broken down and can accumulate
And then see if the muscle strength increases (more Ligand gated Na+ channels open so more likely that end plate potential reaches threshold)
What is the test called to diagnose myasthenia gravis?
Edrophonium test
Sees if facial muscle weakness improved by the ACh esterase inhibitor edrophonium chloride
How is organophosphate poisoning bad?
Permanently inhibit ACh esterase
Where are muscarinic Acetylcholine receptors located?
Following postganglionic parasympathetic neurones on the target tissues
How does the type of synaptic transmission differ between nAChRs and mAChRs?
nAChR = fast synaptic transmission
mAChR = slow synaptic transmission
Why is nAChR fast synaptic transmission?
The receptor and ion channel are the same protein
It is a ligand gated ion channel so depolarisation is fast
Why is mAChR slow synaptic transmission?
mAChR is a G protein coupled receptor
Receptor and ion channel are separate proteins
G protein needs to be activated triggering a cascade of events in the cell leading to the opening of the ion channel
