Neuromuscular junction Flashcards
How is signal passed between nerve and muscle?
At neuromuscular junction onto motor end plate
What is cellular response of depolarisation at end of synaptic bouton?
Depolarisation (influx of Na+) causes Ca2+ V gated channels to open
Ca+ enters synaptic bouton
What does increase in Ca2+ mean in synaptic bouton?
Neurotransmitter is released via exocytosis
Levels of Ca2+ normally inside
Normally very low in cells
Ca2+ influx can raise internal concentration significantly
what does increasing frequency of action potentials do?
Increases the amount of Ca2+ entry and increases transmitter released
structure of V gated Ca2+ channels
similar to na+
1 a subunit: 4 sections
membrane spanning
What blockers block L type Ca2+ channels?
DHP (dihydropyridines)
what is DHP used for?
Regulating BP
Blocks L type Ca2+ cells present in smooth muscle cells of vessels (less contraction = lower BP)
Subunits associated with Ca2+ and Na+ channels
phosphorylation sites
increase ability to open (more likely to contract)
what does Acetylcholine esterase do?
breaks down Ach - not high concentrations in synaptic cleft
how does Ca2+ enter cell?
through V gated Ca2+ channels
what does Ca2+ bind to when in cell?
Synaptotagmin
What does Ca2+ binding with synaptotagmin cause?
Vesicles bought close to membrane
Interact with snare complex
What does snare complex do?
Makes fusion pore
Ach exits via this pore
nAchR (nicocinic Ach receptor) type
ligand gated
permeable to cations
What does nAchR permeability mean?
allows Na+ into cell and K+ out of cell
Driving force of Na+ is higher due to membrane potential being nearer Ek
What occurs when Na+ moves into cell via nAchR?
Membrane reaches threshold and depolarises end plate
What is transmitter release dependent on?
Ca2+ entry to cell
If you lower external Ca2+ conc, end plate potentials decrease in amplitude
How does end plate potential activate muscle action potential?
brief depolarisation activates adjacent Na+ channels (charge spreads)
propagates along muscle fibre
How does curare cause paralysis?
Blocking transmission between nerve and muscle
used in hunting
2 types of nicotinic blockers
competitive blocker
Depolarizing blocker
Competetive blocker example
D-tubocurarine (d-TC)
how does d-TC work?
Competitively binds to nAchR (receptor site) and prevents Ach from binding
can d-TC effects be overcome?
Yes, increasing Ach concentration
How do depolarising blocks work?
Maintain depolarisation
Fail to activate adjacent Na+ channels as they are inactivated
May get initial quivering but then nothing
Depolarising blocker example
Succinylcholine
When are neuromuscular blockers used?
Surgery - but can look like under general anaesthetic but can still feel pain just cannot move (paralysed)
Myasthenia Gravis
Autoimmune disease targeting nAch receptors
Antibodies attack receptor - loss of function and degradation
End plate potentials cannot reach threshold
Myasthenia Gravis signs/symptoms
weakness
increases with exercise
fatigue
end plate potentials reduced in amplitude = muscle weakness/fatigue
Diagnosis myasthenia gravis
Facial weakness provoked by repeated facial movements
Edrophonium chloride injection (anticholinesterase)
Facial weakness relieved rapidly = positive for myasthenia gravis
Organophosphate poisoning sources
Insecticides
Pentavalent phosphorous compounds
Nerve agents (sarin, Novichok)
Organophosphate poisoning mechanism
Acetylcholinesterase inhibitors form a stable irriversible covalent bond to the enzyme
Ach not broken down
organophosphate symptoms
SLUDGE salivation lacrimation urination defecation gi cramps emesis
Recovery organophosphate poisoning
Synthesis of new actylcholinesterase needed
takes weeks
Other mechanisms of Ach
Binds to muscarinic ach receptors on target tissues of autonomic nervous system
nAchR vs mAchR
nAchR - fast depolarisation as its ligand gated
mAchR - slower response, G coupled proteins which trigger cascade of events in cell
