Neuromuscular Transmission and drugs Flashcards
neuromuscular junction definition
Chemical synapse formed by the contact between a motor neurone and a muscle fibre
Structure of neuromuscular junction
- terminal region of motor neurone has no myelin sheath
- presynaptic neurone formed of a synaptic knob
- contains calcium ion channels
- synaptic cleft separates the axon from the muscle fibre
- sarcolemma at the junction has postjunctional folds to increase the surface area for neurotransmitter release
What is a motor end plate?
The region of the muscle fibre innervated by one nerve
Process of sending an impulse across the NMJ
- action potential depolarises motor axon
- depolarisation opens voltage gated calcium channels in the terminal membrane, causing calcium ions to move in.
- Triggers the fusion of docked synaptic vesicles
- acetylcholine contained is released into the synaptic cleft
- acetylcholine diffuses across the synaptic cleft and binds to the nicotinic receptors on the muscle fibre
- non selective cation channels open and depolarises the membrane in the end plate region
- when threshold is reached, an action potential is generated
What is an EPP?
End plate potential- depolarisation of the muscle region
Synthesis of ACh explained
Synthesised by enzyme choline acetyltransferase from the compounds choline and acetyl-CoA. High uptake of choline from synaptic cleft, often achieving Vmax
How is ACh moved into vesicles?
vesicular ACh transporters uptake ACh using an ATPase.
Release of ACh explained
V-snares bound to the transport vesicles, T-snares present on the cell membrane.
The V and T snares fuse to form a trans-snare complex (snare pin) that allow the acetylcholine to be released.
Release in quanta- each vesicle contains roughly 4 units of ACh
4 snare proteins involved and function
V snare- present on vesicle. Bind to t snares and form trans snare complex.
T snare- present on membrane, bind to v snares to form trans snare complex
Q snare- synaptobrevin and R snare, syntaxin along with V and T assemble to form core snare complex.
What is the process of zippering?
Fusion of V and T thought to lead to a conformational change of the trans snare complex to cis snare complex.
Released energy thought to cause molecular bending stress in the snare motifs and causes mechanical stress.
the energetically unfavourable bending is overcome by the two membranes fusing
ACh action explained
Binds to nicotinic receptors on end plate, which are ligand gated channels and open them. Binds to two cysteine residues forming a specific cys-loop receptor
What happens once ACh is used?
Enzyme acetylcholinesterase, present in the synaptic cleft, hydrolyses the acetylcholine to choline and acetate
Two types of neuromuscular blocking drug + definitions
Depolarising blocking agents- agents that depolarise the sarcolemma persistently which makes the fibre resistant to further stimulation by ACh
Non-depolarising blocking agents- agents that act competitively to block the binding of ACh to its receptors, or blocking the inotropic effect of the ACh receptors
Examples of non-depolarising block agents
Curare and Vecuronium
How does curare work? + medical use
Acts as an nAChR antagonist, due to its similar quaternary amino structural motif.
Used as an anaesthetic
How does Vecuronium work? + medical use
Antagonist for nAChR
Provides skeletal muscle relaxation during surgery or medical ventilation
Examples of depolarising block agents
Suxamethonium
How does suxamethonium work? + medical use
Competitive agonist. Binding results in the opening of the monovalent cation channel
Suxamethonium has a longer duration of action than acetylcholine
It is not hydrolysed by acetylcholinesterase
Used to cause short term paralysis as part of general anaesthesia
Other examples of drugs
vesamicol, botulinum toxin, neostigmine and latrotoxin
How does vesamicol work? medical use
Does not act at ACh receptor
Blocks vesicular ACh transporter that is responsible for carrying ACh into vesicles
Adenocarcinoma in lungs
Latrotoxin function and medical use
Neurotoxin found in the venom of spiders. Alpha latrotoxin forms pores in the presynaptic membrane.
Permeable to calcium ions, so calcium moves in and triggers all the vesicles to exocytose
Botulinum toxin function and medical use
Cleaves snare proteins, preventing the release of ACh
Used for hyperhidrosis, reduction in face wrinkles. Used to treat uncontrolled muscle spasms
How can neuromuscular block be prevented?
Use anti-cholinesterases to prevent the breakdown of acetylcholine, increasing its action at the available (unblocked) nAChRs
Example of an anti cholinesterase + medical use
Neostigmine
Blocks the active site of cholinesterase so the enzyme can no longer break down acetylcholine.
Used to treat Myasthenia Gravis
Explain Myasthenia Gravis
Autoimmune synaptopathy - immune system generates antibodies that attack the body tissues.
Specifically attack MuSK or nAChR, preventing the formation of action potentials.
Can cause drooping eyelids, double vision, trouble talking and trouble walking.
What replaces neuromuscular junctions in both smooth and cardiac muscle?
Cardiac- en passant junctions
smooth - axons with varicosities
Explain en passant junctions
One neurone joins another at a place beside the axon terminal. The synapses are present at the stem of the axon. Axoaxonic
Axoaxonic definition
one axon joins to another along its length
Explain varicosities
Many peripheral nerves have swellings termed varicosities, from which neurotransmitter is released at varying distances from the effector cells.
No specialised post junctional structure, however neurotransmitter receptors accumulate on cell membranes close to the junctions
