Lecture 10: Skeletal Muscle Neurophysiology 2

Question 1

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?

Answer 1

less

Question 2

Similar to neurons, muscle cells maintain a hyperpolarised resting membrane potential, true or false?

Answer 2

true

Question 3

Are muscle cells relatively negative or positively charged compared to the outside of the cell?

Answer 3

negatively charged

Question 4

Describe the NMJ sequence of events

Answer 4

1. action potential in the axon which spreads into the nerve terminal
2. this causes the voltage gates Ca2+ channels to open
3. Ca2+ triggers vesicle fusion and ACh is released and diffuses across the synaptic cleft
4. ACh binds to nAChR on the muscle fibre
5. nAChR channels open and Na+ enters the muscle fibre
6. the influx of Na+ ions cause a local depolarisation in the muscle fibre which spreads to the extrajunctional membrane
7. this depolarisation opens voltage-gated Na+ channels which causes an action potential in the muscle to be triggered
8. the action potential propagates along the fibre
9. ACh is degraded by ACHE

Question 5

Where are most of the voltage gated Ca2+ ion channels located?

Answer 5

mostly near the active zone, next to the vesicles

Question 6

Why is it important for the voltage gated Ca2+ ion channels to be near the active zone?

Answer 6

because it means that there is tight coupling between Ca2+ entering and exocytosis

Question 7

What is a features of the synaptic cleft that allows for fast diffusion?

Answer 7

the short distance

Question 8

What receptors does ACh bind to on the muscle fibre?

Answer 8

nicotinic acetylcholine receptors

Question 9

What allows Na+ ions to enter the muscle fibre?

Answer 9

it’s electrochemical gradient which drives it into the cell

Question 10

What does extrajunctional membrane mean?

Answer 10

either side of the NMJ

Question 11

What is meant by there being a high safety factor?

Answer 11

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

Question 12

Why does the ACh being released decrease when there is a burst of action potentials from the same axon?

Answer 12

because ACh is being released from the axon terminal faster than it is being regenerated

Question 13

What are the two types of acetylcholine receptors?

Answer 13

nicotinic and muscarinic

Question 14

Describe the nicotinic acetylcholine receptor

Answer 14

• 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

Question 15

What type of receptor is the nAChR?

Answer 15

ionotrophic receptor which means that the ion channel is a major part of its structure

Question 16

When does the nAChR open?

Answer 16

when two molecules of ACh bind

Question 17

What is the nAChR permeable to?

Answer 17

it is a non-specific cation channel permeable to both Na+ and K+

Question 18

Why are the nAChR different in the brain and the muscles?

Answer 18

because the subunits can change so there is different combinations of them

Question 19

What determines which ions can go through the channel of nAChR?

Answer 19

the amino acids in the sequence

Question 20

What happens when the nAChR opens?

Answer 20

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

Question 21

What happens when ACh unbinds from the nAChR?

Answer 21

it goes back into its closed resting state

Question 22

What is the desensitised state of the nAChR?

What needs to happen for the receptor to become active again?

Answer 22

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

Question 23

Where are the muscarinic acetylcholine receptors located?

Answer 23

CNS, ANS and smooth muscle

Question 24

Are nAChR in the brain or skeletal muscle more receptive to nicotine?

Answer 24

in the brain

Question 25

What type of receptors are muscarinic receptors?

Answer 25

metabotrophic receptors

Question 26

how do metabotrophic receptors work?

Answer 26

they signal via activating g protein coupled receptor pathways which change the intracellular signalling and can indirectly control the opening of ion channel

Question 27

Where are the muscarinic receptors located?

Answer 27

not in the skeletal muscle but there is lots in the CNS, ANS and smooth muscle

Question 28

Describe the muscarinic receptor

Answer 28

it is in a complex with g-proteins (interacting with the receptor)

Question 29

What happens when the muscarinic receptor binds ACh?

Answer 29

- 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

Question 30

What is an agonist of the nAChR?

Answer 30

nicotine

Question 31

What does it mean to be an agonist of the nAChR?

Answer 31

to activate it

Question 32

What are two antagonists of the nicotinic receptor?

Answer 32

tubocurarine and α-neurotoxins

Question 33

What does it means to be an antagonist of the nAChR What is the effect of this?

Answer 33

it inhibits these receptors which means that (for the case of tubocurarine) that it can cause paralysis by blocking these receptors

Question 34

What is an agonist of the muscarine receptor?

Answer 34

muscarine

Question 35

What is an antagonist of the muscarinic receptor?

Answer 35

atropine

Question 36

What are drugs that inhibit AChE?

Answer 36

edrophonium | pyridostigmine

Question 37

Why would we want to inhibit the AChE?

Answer 37

because it prevents the breakdown of ACh to keep level high in the synaptic cleft

Question 38

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

Answer 38

the first statement is false and the second statement is true

Question 39

What is myasthenia gravis and what causes it?

Answer 39

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

Question 40

What happens when there is reduced NMJ function?

Answer 40

there is muscle weakness

Question 41

Where is myasthenia gravis most prominant?

Answer 41

in frequently used muscles

Question 42

In myasthenia gravis, why do syptoms come on with sustained contraction (ie. in muscles that are used frequently)?

Answer 42

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

Question 43

Why do AChE blockers help maintain the symptoms of MG?

Answer 43

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