Lecture 10: Skeletal Muscle Neurophysiology 2 Flashcards
Does tissue that requires fine control require an axon of a motor neuron to innervate more or less muscle fibres compared to tissue what does not require fine control?
less
Similar to neurons, muscle cells maintain a hyperpolarised resting membrane potential, true or false?
true
Are muscle cells relatively negative or positively charged compared to the outside of the cell?
negatively charged
Describe the NMJ sequence of events
- action potential in the axon which spreads into the nerve terminal
- this causes the voltage gates Ca2+ channels to open
- Ca2+ triggers vesicle fusion and ACh is released and diffuses across the synaptic cleft
- ACh binds to nAChR on the muscle fibre
- nAChR channels open and Na+ enters the muscle fibre
- the influx of Na+ ions cause a local depolarisation in the muscle fibre which spreads to the extrajunctional membrane
- this depolarisation opens voltage-gated Na+ channels which causes an action potential in the muscle to be triggered
- the action potential propagates along the fibre
- ACh is degraded by ACHE
Where are most of the voltage gated Ca2+ ion channels located?
mostly near the active zone, next to the vesicles
Why is it important for the voltage gated Ca2+ ion channels to be near the active zone?
because it means that there is tight coupling between Ca2+ entering and exocytosis
What is a features of the synaptic cleft that allows for fast diffusion?
the short distance
What receptors does ACh bind to on the muscle fibre?
nicotinic acetylcholine receptors
What allows Na+ ions to enter the muscle fibre?
it’s electrochemical gradient which drives it into the cell
What does extrajunctional membrane mean?
either side of the NMJ
What is meant by there being a high safety factor?
Lots of ACh being released which causes this very large depolarisation which means that one AP in the axon will almost always trigger an AP in the muscle
Why does the ACh being released decrease when there is a burst of action potentials from the same axon?
because ACh is being released from the axon terminal faster than it is being regenerated
What are the two types of acetylcholine receptors?
nicotinic and muscarinic
Describe the nicotinic acetylcholine receptor
- five subunits form a channel
- each subunit is made of 4 transmembrane domains
- the nAChR are different in the brain and the muscles
- they are normally closed
What type of receptor is the nAChR?
ionotrophic receptor which means that the ion channel is a major part of its structure
When does the nAChR open?
when two molecules of ACh bind
What is the nAChR permeable to?
it is a non-specific cation channel permeable to both Na+ and K+
Why are the nAChR different in the brain and the muscles?
because the subunits can change so there is different combinations of them
What determines which ions can go through the channel of nAChR?
the amino acids in the sequence
What happens when the nAChR opens?
it is now activated
Na+ flows in, K+ can flow out but the overall effect is an influx of positive ions into the muscle fibre so there is a depolarisation
What happens when ACh unbinds from the nAChR?
it goes back into its closed resting state
What is the desensitised state of the nAChR?
What needs to happen for the receptor to become active again?
if ACh remains bound for too long, the channel becomes desensitised so the gate closes despite ACh being bound
to become active, ACh needs to unbind for it to return to its resting state to then be activated again
Where are the muscarinic acetylcholine receptors located?
CNS, ANS and smooth muscle
Are nAChR in the brain or skeletal muscle more receptive to nicotine?
in the brain
What type of receptors are muscarinic receptors?
metabotrophic receptors
how do metabotrophic receptors work?
they signal via activating g protein coupled receptor pathways which change the intracellular signalling and can indirectly control the opening of ion channel
Where are the muscarinic receptors located?
not in the skeletal muscle but there is lots in the CNS, ANS and smooth muscle
Describe the muscarinic receptor
it is in a complex with g-proteins (interacting with the receptor)
What happens when the muscarinic receptor binds ACh?
- there is a conformational change which is relayed to the g-proteins and this changes the affinity of the g-α subunit so that it exchanges a GDP for a GTP
- with the GTP, the α subunit can now dissociate from the other g-proteins to regulate other processes in the cell
- one of those is directly interacting with ion channels (in the case of the muscarinic receptors, it will open a K+ channel) to hyperpolarise the cell
What is an agonist of the nAChR?
nicotine
What does it mean to be an agonist of the nAChR?
to activate it
What are two antagonists of the nicotinic receptor?
tubocurarine and α-neurotoxins
What does it means to be an antagonist of the nAChR What is the effect of this?
it inhibits these receptors which means that (for the case of tubocurarine) that it can cause paralysis by blocking these receptors
What is an agonist of the muscarine receptor?
muscarine
What is an antagonist of the muscarinic receptor?
atropine
What are drugs that inhibit AChE?
edrophonium
pyridostigmine
Why would we want to inhibit the AChE?
because it prevents the breakdown of ACh to keep level high in the synaptic cleft
Acetylcholine must be generated by actylcholinesterase in the axon of the NMJ BECAUSE choline (rather than acetylcholine) is pumped back into the axon through the choline transporters
the first statement is false and the second statement is true
What is myasthenia gravis and what causes it?
It is an autoimmune disease of the NMJ caused by antibodies binding to the nAChR and recruiting other immune cells to cause an inflammatory response.
This means that there is a reduction in the receptor number, receptors are blocked and there is damage of the NMJ
What happens when there is reduced NMJ function?
there is muscle weakness
Where is myasthenia gravis most prominant?
in frequently used muscles
In myasthenia gravis, why do syptoms come on with sustained contraction (ie. in muscles that are used frequently)?
In the normal NMJ, a rapid sequence of many APs in the nerve causes a slight depletion of the releasable pool of vesicles and so with every successive AP, there is less ACh released.
However, normally, still enough ACh is released by a single AP to initiate an AP in the muscle fibres (due to the high safety factor)
However, when the number of receptors is reduced (like in MG), this normal drop in ACh for later impulses may cause a failure of transmission
Why do AChE blockers help maintain the symptoms of MG?
because these stop AChE working which means that there is a delay in the breakdown of ACh so the levels of ACh remain higher in the synaptic cleft
