Session 5.3 Neuromuscular junction

Question 1

what is the purpose of a neuromuscular junction

Answer 1

the synapse between a nerve and skeletal muscle fibre

Question 2

what happens as action potential reaches nerve terminal

Answer 2

when action potential arrives at nerve terminal, lots of voltage gated calcium ion channels. when open causes calcium entry which causes increase in calcium concentration which causes release of neurotransmitter

Question 3

what is calcium concentration inside axon

Answer 3

low so any change is significant

Question 4

what does increased frequency of action potentials cause

Answer 4

increased amount of nerve terminal calcium entry and so more transmitter released

Question 5

what is the structure of voltage gated calcium ion channels

Answer 5

• similar to sodium gated ion channels
• one alpha subunit = functional calcium channel
• consists of 4 repeats
• an S4 region which has positive amino acids - detect changes in membrane potential and cause a conformational change, when depolarised = open
• has a alpha subunit which forms pore to be used as functional channel
• generally diverse with different isoforms, eg: L sensitive to DHP which blocks the calcium channels, reducing blood pressure

Question 6

how are sodium and calcium ion channels’ activity altered

Answer 6

can alter the activity of a channel = alter the properties

• different subunit compositions
• also have phosphorylation sites on inside which can modify activity of channel and glycosylation sites on outside

Question 7

what is the structure of a neuromuscular junction

Answer 7

nerve terminal which vesicles fuse with
synaptic cleft
postsynaptic muscle membrane with post junctional folds and ach receptors

Question 8

how is transmitter released

Answer 8

1. calcium enters through calcium ion channels
2. calcium binds to synaptotagmin
3. vesicles are brought close to the membrane
4. snare complex makes a fusion pore
5. transmitter released through this pore by exocytosis into synaptic cleft

Question 9

how does depolarisation occur

Answer 9

Transmitter is in synaptic cleft, it diffuses along and combines with nicotinic acetylcholine receptor (ligand gated ion channel), 2 acetylcholine required to open pore of channel, sodium and potassium can flow through, depolarisation (sodium enters) = produces end plate potential (-10mV). this will activate adjacent sodium ion channels due to local spread of charge, so reaches threshold which initiates an action potential adjacent to the end plate which propagates along muscle fibre which causes a contraction

Question 10

why does sodium move in for depolarisation

Answer 10

a larger gradient for sodium to move into cell than potassium to move out of the cell as Ek is closer to resting membrane potential

Question 11

if you decrease concentration of calcium on outside

Answer 11

end plate potential amplitude decreases as

less calcium entry so less activation and less transmitter released

Question 12

how and why is acetylcholine degraded

Answer 12

acetylcholine esterase

so remove stimulation on receptors in time for next action potential to come along

Question 13

group of action potentials=

Answer 13

stronger contraction

Question 14

what is crude curare

Answer 14

causes paralysis in animals, but human can eat

by blocking transmission between nerve and muscle

Question 15

how does paralysis occur

Answer 15

blocks nicotinic ach receptors
block end plate potential
no action potential in skeletal muscle
1. competitive blocker = interact with receptor and so receptor not open
2. depolarisation blocker = cause opening of receptor when bound which will lead to inactivation of sodium channels which will cause the receptor to become desensitised

Question 16

how does competitive block work by d-TC

Answer 16

2 curare binds to sites where acetylcholine wants to bind to, so not bind to site so smaller end plate potential
only one acetylcholine required to out compete curare so if increase concentration of acetylcholine can overcome - depends on relative concentration of both

Question 17

how does depolarising block work by succinylcholine

Answer 17

continually active nicotinic receptors by binding, opening these receptors, maintained depolarisation of end plate potential, local currents spread, open sodium ions, but become inactivated with depolarisation so not able to activate them and cause action potential

Question 18

where are neuromuscular agents used

Answer 18

in operations
in addition with anaesthetics to cause temporary paralysis so muscles become relaxed which makes surgery easier, however, can still feel pain but can’t move

Question 19

what diseases are associated with defects of the neuromuscular junction

Answer 19

mayasthenia gravis - autoimmune disease which targets nicotinic acetylcholine receptors. so less functional receptors on membrane size of end plate potential smaller so end plate potential fails to reach threshold potential so no action potential. due to antibodies directed again the receptor which cause mediated lysis and receptor degradation
- weakness which increases with exercises

Question 20

how do you diagnose myasthenia gravis

Answer 20

edrophonium test
give drug edrophonium, a short acting antiacetylcholinic esterase, blocks enzyme so increase concentration of acetylcholine in synaptic cleft so maybe overcome as can increase amplitude of end plate potential as can bind with as many functional receptors as possible, then control of eyelids

Question 21

what other diseases attack neuromuscular junction

Answer 21

organophosphate poisoning - used as insecticides, accidental poisoning, nerve agents
act as acetylcholinesterase inhibitors to form a stable irreversible covalent bond to the enzyme. recovery takes weeks to replace acetylcholinesterase enzymes

Question 22

what is another example of an acetylcholic receptor

Answer 22

muscarinic acetylcholinic receptor
found on target tissue such as gland cells, gut, smooth muscle cells
SLOWER RESPONSE, COUPLED G PROTEIN WHICH TRIGGERS A CASCADE OF EVENTS, ACTIVATION OF G PROTEIN, MODIFIED BY G ALPHA OR G GAMMA

Question 23

where is the nicitonic acetylcholine receptor found and key features

Answer 23

skeletal muscle membrane and post-ganglionic membrane at junction. they are LIGAND GATED and FAST DEPOLARISATION AT END PLATE, SODIUM INFLUX, POTASSIUM OUT