Session 5.3 Neuromuscular junction Flashcards
what is the purpose of a neuromuscular junction
the synapse between a nerve and skeletal muscle fibre
what happens as action potential reaches nerve terminal
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
what is calcium concentration inside axon
low so any change is significant
what does increased frequency of action potentials cause
increased amount of nerve terminal calcium entry and so more transmitter released
what is the structure of voltage gated calcium ion channels
- 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
how are sodium and calcium ion channels’ activity altered
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
what is the structure of a neuromuscular junction
nerve terminal which vesicles fuse with
synaptic cleft
postsynaptic muscle membrane with post junctional folds and ach receptors
how is transmitter released
- calcium enters through calcium ion channels
- calcium binds to synaptotagmin
- vesicles are brought close to the membrane
- snare complex makes a fusion pore
- transmitter released through this pore by exocytosis into synaptic cleft
how does depolarisation occur
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
why does sodium move in for depolarisation
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
if you decrease concentration of calcium on outside
end plate potential amplitude decreases as
less calcium entry so less activation and less transmitter released
how and why is acetylcholine degraded
acetylcholine esterase
so remove stimulation on receptors in time for next action potential to come along
group of action potentials=
stronger contraction
what is crude curare
causes paralysis in animals, but human can eat
by blocking transmission between nerve and muscle
how does paralysis occur
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
how does competitive block work by d-TC
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
how does depolarising block work by succinylcholine
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
where are neuromuscular agents used
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
what diseases are associated with defects of the neuromuscular junction
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
how do you diagnose myasthenia gravis
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
what other diseases attack neuromuscular junction
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
what is another example of an acetylcholic receptor
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
where is the nicitonic acetylcholine receptor found and key features
skeletal muscle membrane and post-ganglionic membrane at junction. they are LIGAND GATED and FAST DEPOLARISATION AT END PLATE, SODIUM INFLUX, POTASSIUM OUT
