Neuromuscular junction Flashcards
What happens at the end of the nerve terminal?
Release of neurotransmitters
What do neurotransmitters do?
Carry the signal across the synaptic cleft (gap between the neuron and the post synaptic effector cell)
- presynaptic nerve terminals -> postsynaptic membrane
What can the neurotransmitter acting on the receptors cause?
Excitation or inhibition
What is the neuromuscular junction?
The synapse between a neurone and a skeletal muscle fibre
Name the 5 steps that exist within the synaptic transmission at the neuromuscular junction
1- Synthesis 2- Storage (protect and package) 3- Release 4- Activation 5- Inactivation
How can drugs enhance synaptic transmission directly?
Direct stimulation of post-synaptic receptors by-
- the natural transmitter
- analogues
How can drugs enhance synaptic transmission indirectly?
- Increased transmitter release
- inhibition of transmitter removal
How can drugs inhibit synaptic transmission?
1) Blocking synthesis, storage or release from the pre-synaptic neurone
2) Blocking postsynaptic receptors
What can drugs acting directly on receptors be divided into?
Agonists and antagonists
What are agonists and their two impotant properties?
Drugs, hormones or transmitters which bind to specific receptors and initiate a conformational change in the receptor resulting in a biological response
Affinity and Efficacy
What is the definition of affinity?
The ability of agonists to bind to receptors
What is the definition of efficacy?
The ability of an agonist, once bound to a receptor, to initiate a biological response
What do antagonists do?
Bind to receptors but do not activate them
Block receptor activation by agonists
What properties do antagonists have?
Affinity but not efficacy
What is a competitive antagonist?
Competes with the agonist for the agonist binding site on the receptor
What is the neurotransmitter at the NMJ?
Acetylcholine
What is the name of the synapses that synthesise and release acetylcholine? What are the receptors incolved called?
Cholingeric
Cholinoceptors
What are the two classes on cholinoceptors and what are they activated by?
Nicotinic cholinoceptor (nAChRs) - nicotine Muscarinic cholinoceptors- muscarine
What is fast synaptic transmission mediated by?
Transmitter-gated ion channels
What does Ash released from a vesicle cause?
a miniature endplate potential
- activates many nicotinic ACh receptors
What occurs upon activation of the nicotinic cation channels?
They open and Na+ ions flux into the muscle fibre to cause a local depolarisation at the endplate region
What does exocytosis and endocytosis do?
Exo- vesicle fusion
Endo- recovery of vesicular membrane after fusion
What is essential for neurally-evoked neurotransmitter release?
Localised calcium entry via voltage-gated calcium channels
What blocks the voltage-gated calcium ion channel?
Magnesium
What does a high Mg2+ low Ca2+ extracellular solution result in?
Reduces the app to below the threshold for firing an action potential
What suggests that the release of a neurotransmitter at the NMJ is quantal?
The amplitude of the app is a multiple of the amplitude of the meep, with the smallest epp amplitude equal to that of the mepp amplitude
What is the quantal content equation?
QC= mean EPP amplitude (mV) / mean MEPP amplitude (mV)
number of vesicles/stimulus
How do MEPPs and EPPs occur?
MEPPs- occur spontaneuosly without nerve stimulation
EPPs- occur in response to motor nerve stimulation
In MEPPs what happens upon nerve stimulation?
MEPPs summate to give an end plate potential (EPP) which initiates an action potential -> muscle contraction
What occurs in the first step of the synthesis stage?
Choline acetyl transferase (CAT) synthesises ACh from precursors choline and Acetyl Coenzyme A from mitochondria
What is the reuptake of choline dependant on and blocked by in the synthesis stage?
Na+ dependant and blocked competitively by hemicholinium 3?
What happens to the amplitude of the epp and mepp due t less ACh in each vesicle in the synthesis stage?
The amplitude is decreased to a similalr extent ie. n change in quantal content
What is a Tetrodotoxin (TXX)?
A powerful toxin produced by bacteria and concentrated organs of the puffer fish e.g liver
What happens when the toxin TXX is exposed to humans? How does it act?
Causes paralysis of the diaphragm leading to respiratory failure
Acts like a local anaesthetic lidocaine, much more potent
TXX blocks Na+ channels, what does this mean for action potentials and epp?
No action potential- no release, no epp
What channel does conotoxin block? And what happens to the quantal content when the epp amplitude decreases?
Voltage gated Ca+ channels
Decreased quantal content, no change in the mepp ampitude
What channel is blocked by the toxin dendrotoxin? And what happens to the quantal content?
Blocks voltage-gated K+ channels
Quantal content is increased due to increased mepp and epp amplitude
What is the toxin Botulinum used for clinically and cosmetically?
Clinically- Treat a variety of muscle disorders, chronic migraine and excessive sweating, neuropathic pain
Cosmetically- Botox
How does the toxin Botulinum act?
What happens to the mepp, epp and quantal content?
Blocks vesicle fusion by cleaving a vesicular protein required for exocytosis- decreased release
mepp- no change
epp- decreased amplitude
quantal content - decreased
What does non-depolarising neuromuscular blockers compete with ACh for?
Binding to skeletal muscle nicotinic ACh receptors
What do non - depolarising neuromuscular blockers reduce the amplitude of for muscle fibre action potential generation?
Reduce amplitude of endplate potential (epp)
In amuscle fibre action potential, what happens when there is no action potential?
No muscle contraction occurs
What is tubocurarine used for?
And what does it allow the surgeon to conduct?
Used during surgery to produce skeletal muscle paralysis
Allows surgeon to conduct intricate surgery without the complexity of unwanted skeletal muscle contracion
What does the patient require after having tubocurarine? Why?
Requires artificial respiration as the diaphragm muscle is also paralysed
How is the muscle block that tobocurarine causes, reversed?
Anticholinesterases
What toxin cant be reversed by washout or anticholinesterases?
alpha-Bungarotoxin
What is used for rapid tracheal intubation and to prevent violent muscle contraction?
suxamethonium
Link the NMJ nAChRs to whether they are agonists, competitve antagonist or irreversible antagonist:
- ACh and nicotine
- Suxamethonium
- Tubocurarine
- a-Bungarotoxin
ACh and Nicotine- Agonist
Suxamethonium- Agonist
Tubocurarine- Competitive antagonist
a-Bungarotoxin- Irreversible antagonist
How is ACh terminated in the inactivation stage and what is it broken down into?
Terminated by an enzyme acetylcholinesterase
Breaks down ACh to acetate and choline
What effects do drugs that inhibit AChE have an the effects of ACh?
Increase the effects of ACh
-Present at cholinergic synapses
- Bound to the postsynaptic membrane in the synaptic cleft
These are characteristics of what?
“True” acetylcholinesterase
- Widely distributed and found in plasma
- Important in inactivating the depolarising neuromuscular blocker, suxamethonium
These are characteristics of what?
Pseudo-cholinesterase
True or false, both “true” and pseudo cholinesterase’s are inhibited equally by most clinically-relevant anticholinesterases
True
Name two examples of anti cholinesterase drugs
Neostigmine
Edrophonium
An example of organophosphate is nerve gas agents such as novichok. How can these be reversed?
Atropine
Oximes
