Neuromuscular Junction Flashcards
What is a motor unit?
The motor neurone and all of the skeletal muscle fibres that are innervated by that motor neurone’s axon terminals
What happens when the motor neurone of a motor unit fires?
All of the muscle fibres within the motor unit will contract together
How does the size of the motor unit influence the type of control required?
For a forceful contraction there are more nerve endings innervating more muscle fibres
When fine control is required there are less nerve endings and less muscle fibres are innervated
What is the role of gap junctions in the motor unit?
There are no gap junctions between muscle fibres
The action potential does not spread between them
Contraction is caused by direct innervation
Why is neuromuscular transmission 1:1?
Every presynaptic action potential will result in one postsynaptic potential
Why is neuromuscular transmission a unidirectional process?
It only happens in one direction
What is the time delay in neuromuscular transmission and why is there a delay?
Inherent time delay of 0.5 to 1 milliseconds
Due to the action potential being transferred from the nerve to the muscle
What is the neuromuscular junction?
It is a specialised region that is found at the synapse between motor neurones and skeletal muscle fibres
Where are the neurotransmitter vesicles found?
They are inside the terminal bouton
They are lined up directly above structures on the postsynaptic cell called postjunctional folds
What are postjunctional folds?
Regions where the neurotransmitter receptors are concentrated
Where are motor neurone cell bodies found within the spinal cord?
Inside the ventral horn
They send out axons via ventral roots to innervate appropriate muscles
How do the motor neurones change in composition as they reach muscle fibres?
The axons of motor neurones are myelinated as they pass through the CNS and into the peripheral nerves
They divide to supply thin unmyelinated fibres
Each fibre can innervate several individual muscle fibre cells
Where in the neurone does neurotransmission occur?
Each axon terminates in a terminal bouton
The nerve is 50 nm above the muscle and does not come into direct contact with it
What is significant about the bouton shape?
It gives a large surface area for neurotransmitter release
What happens when the action potential reaches the terminal bouton?
It causes depolarisation of the presynaptic membrane
Depolarisation causes voltage-gated calcium channels to open
There is an influx of Calcium ions
What is the role of microdomains in chemical transmission?
Increase in Ca2+ concentration can trigger many different cellular cascades
We only want vesicles to be released
Microdomains ensure the increase in Ca2+ is localised to the area around the vesicles
What happens in chemical transmission when calcium ions enter the bouton?
They cause the fusion of neurotransmitter vesicles with the presynaptic membrane
The neurotransmitter is released by exocytosis into the synaptic cleft
What happens after acetylcholine is released into the synaptic cleft?
Acetylcholine will bind to nicotinic receptors on the muscle cell membrane
Nicotinic receptors are activated allowing Na+ to enter the muscle cell and cause membrane depolarisation
Why are vesicles within the synaptic terminal lined up directly above post-junctional folds?
The post-junctional folds are on the postsynaptic membrane
The neurotransmitter receptors are concentrated here
Why are some vesicles held back in reserve?
Vesicles are pre-docked and lined up in an ordered way
The ones in reverse will come forward to replace the docked vesicles as they release their content
What is the basal lamina and what is its role in the synaptic cleft?
It is a layer of extracellular matrix that is secreted by epithelial cells
It provides support within the synaptic cleft
Acetylcholinesterase is attached to the basal lamina
Why is the nicotinic receptor described as heteromeric?
It is made from 5 subunits and each subunit is of a different molecular type
Why are there nicotinic receptors with different characteristics?
The exact combination of numerous subunit types and subtypes will differ in different tissues
How many subunits make up a nicotinic receptor?
5 subunits
Each subunit forms 4 transmembrane spanning segments
How is the nicotinic receptor activated?
The 2 alpha subunits have ACh binding sites
2 molecules of ACh must bind to the receptor before it is activated
Binding of ACh allows the central ion pore to open
What is one quantum?
The contents of one synaptic vesicle
Around 5,000 molecules of acetylcholine
How many receptors are activated by one vesicle of ACh?
Release of acetylcholine from one vesicle can activate 1,000 - 2,000 receptors
What is a miniature end plate potential?
It is the depolarisation produced by a single quantum of acetylcholine
This causes a local depolarisation of 0.5 mV
What is meant by a MEPP being produced randomly?
It can be produced without an action potential or calcium influx
You cannot get parts of a quantum released, only multiples of one
How do end plate potentials arise from MEPPs?
MEPPs have an additive effect
They become EPPs when the action potential causes the release of many vesicles
How does an EPP lead to an action potential?
When EPPs cause the membrane to reach the threshold value, voltage-gated ion channels in the postsynaptic membrane will open
There is an influx of sodium ions
The action potential leads to muscle contraction
How is acetylcholine broken down after depolarisation of the postsynaptic cell?
It dissociates from the receptor when it is hydrolysed by acetylcholinesterase
What is ACh broken down into?
Acetylcholine is hydrolysed into acetate and choline
The synaptic knob reabsorbs choline from the synaptic cleft
How is acetylcholine synthesised?
Acetate reacts with co-enzyme A to form acetyl-CoA
Acetyl-CoA reacts with choline to form acetylcholine
How is choline transported into the neurone?
It is derived from the diet
It is taken up by the neurone through a sodium-dependent choline transporter
Where does acetyl-CoA come from?
It is synthesised from glucose and/or fatty acids during the Krebs cycle
Why does ACh synthesis take place in the cytoplasm?
There are choline acetyl-transferase enzymes in cholinergic neurones
Which ion is needed to concentrate ACh into vesicles?
ACh being concentrated into vesicles is coupled to the counter transport of H+
Why is H+ needed to concentrate ACh into vesicles?
The sodium-dependent ACh transporter is a cotransporter
It moves H+ down a CG out of the vesicle
A molecule of ACh is transported into the vesicle
Why is concentrating ACh into vesicles an energy dependent process?
The creation of the H+ gradient is an active process
What is the role of synapsin?
Reserve vesicles are anchored near the active zone by synapsin
Synapsin tethers the reserve vesicles to actin filaments
Why does docking of vesicles occur?
When the v-Snare protein on the vesicle binds to the t-Snare on the membrane at the active zone
What happens to the products of ACh breakdown?
Choline is taken up into the nerve terminal by cotransport with Na+
Acetate is excreted as a waste product as it is broken down to water and carbon dioxide
What happens to the vesicles after the ACh has been released?
They become part of the membrane through endocytosis
They become clathrin coated and internalised
The vesicle fuses with the endosome leading to the production of new vesicles through budding
Why is neuromuscular block used clinically?
It is used as a supplement to anaesthesia to produce paralysis
What is a problem with giving the appropriate dose of neuromuscular-blocking drug?
It may paralyse the muscles required for breathing
Mechanical ventilation should be available to maintain adequate respiration
What is Tubocurarine?
It is a non-polarising competitive nAChR antagonist
How does a non-polarising competitive nAChR work?
It competes with ACh for the binding sites on the nicotinic receptor
This causes muscle paralysis to occur gradually
How is Tubocurarine counteracted?
Paralysis can be overcome by increasing ACh concentration
Acetylcholinesterase is inhibited to achieve this
It is a competitive drug
How does Tubocurarine affect the motor end plate?
It does not depolarise it
What happens if small and large doses of Tubocurarine are given?
At small clinical doses it predominantly acts on the nicotinic receptor to block binding of ACh
At higher doses is can block pre-junctional Na+ channels
This will decrease ACh release
What are the side effects of Tubocurarine and why?
Hypotension and bronchospasm
It increases histamine release which is a vasodilator
What is a therapeutic use of Tubocurarine and what is its time of onset and duration of action?
It is used in surgery
It has a slow onset of < 5 mins
It has a long duration of action of around 30 mins
How many ACh receptors need to be blocked for neuromuscular conduction to fail?
Why does it fail?
70-80% of receptors need to be blocked
EPPs can still be detected but they are too small to reach the threshold potential needed for activation of muscle fibre contraction
What is Succinylcholine?
A depolarising nAChR agonist
How do depolarising nAChR agonists work?
They depolarise the motor end plate
This causes persistent depolarisation of the neuromuscular junction
What are the 2 phases of persistent depolarisation of the neuromuscular junction?
Phase I - depolarisation
Phase II - desensitising
What happens during the depolarisation phase caused by Succinylcholine?
The membrane is depolarised by opening nAChR channels
Causes a brief period of muscle fasciculation (twitching)
After sufficient depolarisation has occurred, phase II sets in
What happens during the desensitising phase caused by Succinylcholine?
End plate eventually repolarises
Succinylcholine is not metabolised as quickly as ACh so it continues to occupy the receptor
The muscle is no longer responsive to ACh
Full neuromuscular block is achieved that leads to flaccid paralysis
When is Succinylcholine used and what is the adverse effect?
It is used in surgery
It is short acting so is given continuously through IV
If it is administered with halothane, genetically susceptible people will experience malignant hyperthermia
What are Neostigmine and Edrophonium?
Cholinesterase inhibitors
How do cholinesterase inhibitors work?
They inhibit acetylcholinesterase
This prevents the breakdown of ACh so the level and duration of action of ACh is increased
What is the main use of Neostigmine?
Treatment for myasthenia gravis
It increases neuromuscular transmission
What is the main use of Edrophonium?
Diagnosis of myasthenia gravis
What are other uses of cholinesterase inhibitors?
They are an antidote for non-depolarising blockers such as Tubocurarine
Treatment for glaucoma
Treatment of postural tachycardia syndrome
How do cholinesterase inhibitors have adverse effects on other parts of the body?
They do not only act on nicotinic receptors
They also act on receptors on the muscles that respond to ACh
How do cholinesterase inhibitors act on the parasympathetic nervous system?
They can cause abdominal cramping, diarrhoea, salivation and incontinence
Why are cholinesterase inhibitors used in insecticides and weapons?
They act as nerve agents
They are stable, easily dispersed, highly toxic and have rapid effects through the skin or via respiration
What are the immediate symptoms of nerve agents?
runny nose watery eyes drooling constriction of pupils eye pain difficulty breathing confusion muscle weakness
How do nerve agents usually cause death?
Asphyxia due to the inability to control muscles involved in breathing
It can cause death within 1 to 10 minutes
What is atropine used for?
It is an antidote used for nerve agents
What do tetanus and botulinum toxins do to the NMJ?
They reduce the probability of neurotransmitter release
They prevent vesicles from binding to the pre-synaptic membrane
How do botulinum toxins work?
It cleaves SNARE proteins that are involved in fusing synaptic vesicles to the plasma membrane
Cleavage of SNARE proteins inhibits ACh release
What does Tetrodotoxin do to the NMJ?
It binds to muscle Na+ channels to block activation
This prevents presynaptic terminal depolarisation and affects the amount of ACh released
What is Lambert-Eaton syndrome?
A presynaptic condition that leads to reduced ACh release
It is a rare autoimmune response that inhibits Ca2+ channels in the presynaptic membrane
Why does Lambert-Eaton syndrome affect muscles?
There is no calcium influx so there is a reduced probability of vesicle release
When no ACh is released, there is no muscle contraction
How is Lambert-Eaton syndrome usually characterised?
Fatigue, weakness in limb muscle groups, autonomic dysfunction and abnormal reflexes, dry mouth
Does not usually affect respiratory, facial or eye muscles
What age group is Lambert-Eaton syndrome usually observed in?
What do most of these patients suffer from?
It is usually observed in middle aged and older individuals
About half of the patients will have a small cell lung cancer
How is Lambert-Eaton syndrome diagnosed?
Electromyography
This involves applying electrical impulses to nerves and measuring the electrical response of the muscle
After a suspected diagnosis, what techniques are used to confirm Lambert-Eaton syndrome?
Often symptoms are worse in the morning
Chest x-rays are used for possible lung malignancy
Antibodies are used to look for Ca2+ channels
How is Lambert-Eaton syndrome treated?
If there is an underlying malignancy, treatment will resolve the symptoms
Immunosuppressants such as corticosteroids are used
Amifampridine is used
How does Amifampridine work?
It blocks potassium ion channels
This increases the duration of the action potential so more ACh is released
What is myasthenia gravis?
It is a postsynaptic disease that involves an immune response against nicotinic receptors
If there are no receptors, the NMJ is less responsive to the ACh that is released
What are the symptoms of myasthenia gravis?
Muscle weakness and fatigue
What are the 2 forms of muscles that myasthenia gravis affects?
Extraocular muscles which control movement of the eye and eyelid elevation
Generalised muscle weakness due to repetitive stimulation decreasing contractile strength
Weakness is greatest at the end of the day or after exertion
How does decreasing the number of AChR affect postsynaptic muscle fibres?
There are fewer AChRs to bind to so the EPPs are smaller
Smaller EPPs means less chance of the postsynaptic muscle fibres being activated
How is Myasthenia Gravis diagnosed?
MRI or CT scan for possible thyoma
Antibodies to ACh receptor
Electromyography
Edrophonium OR Neostigmine test
Often symptoms will improve upon rest
How is Myasthenia Gravis treated?
Treatment is directed at enhancing transmission
Anticholinesterase
Immunosuppressants such as corticosteroids
Some patients have a tumour of the thymus and removing it leads to improvement
How does the age at which men and women are usually affected by myasthenia gravis vary?
Women afflicted at an early age with hyperplasia of the thymus
Men are affected at an older age with cancer of the thymus
