Skeletal Neuromuscular Junction Flashcards
What receptor and NT acts on skeletal muscle in the somatic efferent system?
Acetycholine nicotinic receptors
ACh
What synapse is present on the nerve that affect blood vessels?
What neurotransmitter do nerves release to act on blood vessels in the sympathetic system?
Acetylcholine nicotinic receptors are present in the middle of the neurone
Noradrenaline is released
Neurotransmitters and receptors present in the middle and end of the nerve that affects sweat glands?
Acetycholine nicotinic receptors in the middle
Acetycholine muscarinic at the end
Neurotransmitter and receptor present on the end of the adrenal medulla?
Acetylcholine nicotinic
Neurotransmitter and receptor present in the middle and end of nerves that affect salivary glands of the parasympathetic nervous system?
Acetylcholine nicotinic receptor in the middle
Acetylcholine muscarinic receptor at the end
What is a motor unit of the skeletal neuromuscular junction?
A motor unit is the myelinated motor nerve plus the skeletal muscle fibres it innervates.
- found in the CNS
- motor nerves are wrapped in a myelin sheath
- these control muscle fibres which are focally innervated
- is a very distinct focused region/ highly specialised
What is a neuromuscular junction?
it is a chemical synapse formed between the end of a motor neurone and the skeletal muscle fibre it stimulates/ innervates.
It is at the neuromuscular junction that a motor neuron is able to transmit a signal to the muscle fiber, causing muscle contraction.
Schwann cells in the neuromuscular junction
Terminal schwann cells form lids over the cleft
How big is the hap between the motor nerve and the skeletal muscle fibre/ synapse?
60nm
What is the junctional cleft?
it is the indentation of the muscle fibre/cell which the motor nerve sits into.
What are junctional folds?
The folds of the muscle membrane where there is a high surface area for chemical neurotransmission
Where pre-synaptically and post-synaptically do drugs intefere with neurotransmission?
Presynaptically:
storage
synthesis
release of neurotransmiter
Post synaptically
receptors
removal mechanism
Name the 6 key steps in cholinergic neurotramission
1) Action potential arrives in presynaptic neurone at a speed of 120ms^-1
2) Depolarisation of the nerve terminal
3) Opening of voltage gated calcium channels
4) Calcium entry into the nerve terminal
5) Release of acetylcholine by exocytosis
6) Activation of the post synaptic receptor
Prejunctional events in cholinergic neurotransmission
How is acetylcholine synthesised?
From choline and acetylcoenzyme A (AcCoA)
By action of Choline Acetyl Transferase (CAT)
Ester bond forms between the acetate and the choline
What is the precursor of ACh and how is it taken up into the nerve terminal??
Choline
Taken up into the nerve terminal from the extracellular space by a transporter
Drugs acting pre-junctionally to inhibit cholinergic neurotransmission
What is the MOA of hemicholiniums?
Why does it have no clinical use?
- blocks the transporter that takes up choline
- blocks supply of precursor choline so ACh cannot be manufactured
- form of insecticide
INTEFERES WITH SYNTHESIS - takes a long time to produce any effect
Drugs acting pre-junctionally to inhibit cholinergic neurotransmission
What is the MOA of AH5183 (vesamicol)?
- interferes with storage
- tried to develop it to block neurotransmission
- no clinical use
Drugs acting pre-junctionally to inhibit cholinergic neurotransmission
How do Mg2+/ botulinium toxin work?
Both intefere wiith the release of acetylcholine
- Mg2+ competes with Ca2+ to flow through voltage gated calcium ion channels
- blocks them
- Botulinum toxin acts by binding presynaptically to high-affinity recognition sites on the cholinergic nerve terminals and decreasing the release of acetylcholine, causing a neuromuscular blocking effect.
What bacteria is found in botulinium toxin and what does it give rise to after ingestion?
Contains clostridium botulinium
It gives rise to botulism after ingestion (food poisoning)
How many types of botulinium toxin are there and which is the most common?
7 serotypes from A-G
A being the most common
Is botulinium toxin potent?
Extremely potent
Lethal dose in mice is 10^-12 grams
How does death occur from botulinium toxin?
Due to paralysis of respiratory muscles
Botulinium blocks the release of ACh at skeletal junctions and the diaphragm
What protein does botox destroy in exocytosis?
SNAP-25
Clinically what is botox used for?
- blepharpospasm (involuntary tight closure of eyelids)
- hyperhihdrosis (excessive sweating)
- bladder hyperactivity
- cluster headache
- spasticity associated with cerebral palsy and multiple sclerosis
How is botox applied?
It is a locally administered drug so it minimises side effects
What post junctional events occur at the neuromuscular junction?
Acetylcholine diffuses across the junctional gap and activates nicotinic acetylcholine receptors on the muscle membrane
ACh has to run the gauntlet of the acetylcholinesterase enzyme which breaks the neurotransmitter down
AChE is found in the gap between the muscle nerve and fibre and is tethered to the end of the nerve so is very effective
AChe destroys the ester bond
An action potential in the nerve leads to the release of a puff of ACh which is rapidly removed by AChE
What agonist also activates NACh receptor
nicotine
Describe the structure of the NACh channel
Formed from 5 subunits
alpha, alpha, beta, gamma, e
surrounds a non-selective cation channel that is permeable to Na and K
The e subunit is replaced by a gamma in foetal muscle
When does the NACh channel open?
When two molecules of ACh bind to the protein complex, one to each alpha subunit
Opening of the channel leads to depolarisation of the end plate region of the muscle membrane
What is an EPP?
End plate potential
Form of excitatory post synaptic potential (EPSP)
The depolarisation of the muscle membrane following activation of NAChR
Are the depolarisations of skeletal muscal fibres caused by neurotransmitters binding to postsynaptic membrane in the neuromuscular junction
What is the role of the EPP?
- to depolarise the muscle membrane potential to around -55Mv (threshold for a muscle action potential)
- at -55Mw, voltage- dependent sodium channels open, leading to the rapid all-or-nothing depolarisation of AP
- action potential propagates away from the end plate region, spreading to depolarisation across the muscle surface and leading to contracton
What drugs act post- synaptically to inhibit neuromuscular transmission?
reversible competitive antagonists
non-depolarising relaxants
bind to NAChR so have affinity but no efficacy
prevents AChR from binding
Examples of reversible competitive antagonists at NAChR/ non-depolarising muscle relaxants?
tubocurarine
vecuronium
atracurium
pancuronium
Clinical uses of reversible competitive antagonists?
Used as muscle relaxants during surgery
In combination with general anaesthesia not instead of: as do not cause unconsiousness
Effects last for 15-45 minutes depending on drug
Patients must be artificially ventilated as the diaphragm will not longer be able to contract
Used to stop reflex contractions
Reduces amount of general anaesthesia given
What reverses the effects of reversible competitive antagonists?
neostigmine
Name a depolarising muscle relaxant
suxamethonium (succinylcholine)
MOA of suxamethonium
Acts as an agonist at NAChR
Has both affinity and efficacy, so binds to the receptor, activates it, opens the associated ion channel and depolarises the muscle membrane
depolarisation is prolonged and sodium channels get trapped in the inactivated state and cannot support another action potential
is suxamethonium broken down by AChE?
No, so lingers in the neuromuscular junction producing a prolonged depolarisation which leads to the blockage of neuromuscular transmission
Properties of voltage dependent sodium channels responsible for muscle action potential
On membrane depolarisation produced by ACh, the channels open only transiently before closing into an inactivated state
Once in the inactivated state, the channels cannot reopen, unless they cycle back through the resting state
To allow this to happen, the membrane potential must be returned to its original resting value
The action of AChE means that the depolarisation produced by ACh is very short lived
Allows the action potential to repolarise fully and the voltage- dependent sodium channels to recover from inactivation
Where is suxamethonium used clinically?
muscle relaxation is short lived
use in electroconvulsive therapy and endotracheal intubation
after a single intravenous injection, the effects only last for a few minutes
exception to this, those who have a genetic deficiency of BChE- drug lasts for several hours in these patients
What enzyme does break down suxamethonium
butyrlcholinesterase BChE
enzyme found in blood plasma
Why do patients complain of muscle pain post operatively when they have suxamethonium
initially causes contraction of muscles
drugs that inhibit AChE
- The enzyme acetylcholinesterase can be inhibited by a number of drugs, including neostigmine and edrophonium
- These drugs prevent the breakdown of the neurotransmitter at the neuromuscular junction
- Neostigmine is used clinically to reverse the effects of reversible, competitive antagonists
- It does not reverse the actions of the depolarising muscle relaxant suxamethonium
- In anticholinesterase overdose, paralysis occurs as a result of depolarising block by ACh.
- To overcome the effects of a reversible competitive antagonist- inc. concentration of agonist
What is myasethania gravis?
auto-immune disease characterised by neuromuscular weakness.
Antibodies bind to the α-subunits and ‘cross-link’ adjacent nicotinic receptors
Drugs used in the diagnosis and treatment of myasthenia gravis
- Edrophonium has a very short duration of action (5 minutes) and can be used to diagnose myasthenia gravis
- Neostigmine lasts 4 hours and is used in the treatment of the disease
- The increased concentration of ACh enhances neuromuscular transmission
