Physiology of the Skeletal Neuromuscular Junction Flashcards
What is skeletal muscle innervated by?
Fast conducting ⍺-motor neurones with myelinated axons and cell bodies in the spinal cord or brain stem
What occurs to the myelinated axons of ⍺-motor neurones when they are near the muscle?
The axon divides into unmyelinated branches that innervate an individual muscle fibre
What makes up a motor unit?
The motor neurone and number of muscle fibres that it innervates is the motor unit
What occurs to motor neurone branches at the neuromuscular junction?
The individual branches further divide into multiple fine branches that end in a “terminal bouton” - a chemical synapse with the muscle membrane at the neuromuscular junction
What occurs at the terminal boutons?
Action potentials arising in the cell body are conducted via the axon to the boutons, causing the release of ACh
Name key features of a skeletal neuromuscular junction
- Terminal bouton (and surrounding Schwann cell)
-Synaptic vesicles
-Synaptic cleft
-End plate region (sarcolemma)
Where do synaptic vesicles release their contents?
Active zones
Where are nicotinic ACh receptors located?
Located at regions of the junctional folds that face the active zones
Describe the 3 steps of ACh synthesis and storage
- Choline transporter takes choline into pre-synaptic terminal (symport with Na+)
- ACh is synthesised from choline and acetyl CoA by choline acetyltransferase
- ACh is concentrated in vesicles by the vesicular ACh transporter where they are stored until an action potential arrives
Describe the 3 events that lead to the release of neurotransmitters into the synaptic cleft
- Arrival of the action potential at the terminal leads to the opening of voltage-gated Ca2+ channels (triggered by the depolarisation)
- Influx of Ca2+ into the terminal causes neurotransmitter vesicles to travel to the active zones at the presynaptic membrane
- These vesicles fuse with the cell membrane (exocytosis) causing neurotransmitter release into the synaptic cleft
How many ACh molecules activate each nicotinic ACh receptor?
Two
Describe structure of nAChrs
Pentamers of glycoprotein subunits surrounding a central cation selective pore which contains a gate that opens when ACh binds to the exterior of the receptor
What happens when the gate opens on nAChrs?
-There is simultaneous Na+ influx and K+ efflux
-Because the driving force for Na+ is greater than for K+ at resting membrane potential influx of Na+ is greater than efflux of K+ - rapid depolarising end plate potential is generated by the simultaneous opening of many nAChRs
How is an endplate potential produced?
- The electrical response to one quantum (ACh vesicle) of neurotransmitter is a miniature endplate potential
- Many miniature end plate potentials summate to produce the endplate potential - a graded response
How is a contraction initiated?
An endplate potential that exceeds the threshold triggers the opening of voltage activated Na+ channels around the endplate - initiating an “all or nothing” contraction (normally always occurs)
How many action potentials are needed to bring about a twitch (contraction) of a muscle fibre?
One action potential in the motor nerve triggers one action potential in the muscle and a subsequent ‘twitch’ (contraction) of the muscle fibre
Why are voltage-activated Na+ channels required?
Having a muscle fibre with voltage activated Na+ channels means that the action potential propagates from the endplate over the length of the muscle fibre - contraction
What causes the contraction?
-The muscle action potential causes contraction by release of Ca2+ from the sarcoplasmic reticulum
- The action potential travels over the surface membrane of the muscle fibre and down the T tubules which are close to the SR (where Ca2+ is stored)
How does release of calcium lead to a contraction?
The release of Ca2+ causes contraction by interacting with troponin associated with the myofibrils
What does acetylcholinesterase do?
It hydrolyses ACh into choline and acetate at the endplate membrane
What happens to choline and acetate?
- Choline is taken up by the choline transporter
- Acetate diffuses from the synaptic cleft
Describe in what way acetylcholinesterase is very efficient…
It hydrolyses some ACh molecules even prior to ACh binding to receptors, once unbinding occurs virtually all ACh molecules are hydrolysed
Why is it important that acetylcholinesterase is efficient?
Limits rebinding and means the endplate potential is terminated within a few miliseconds
Name 2 types of therapeutical agents that bind to acetylcholinesterase
-Anti-cholinesterases (reversibly bind)
-Insecticides and nerve gases used in war/terrorism (irreversibly bind)
What are symptoms of neuromytonia (or Isaac’s syndrome)?
-Cramps
-Stiffness
-Myotonia (slow relaxation)
-Fasiculations (muscle twitches)
What occurs in neuromytonia? What does repetitive firing in motor neuroneslead to?
-Can be acquired, usually autoimmune
-Antibodies against voltage-activated K+ channels in the motor neurone disrupt functioning resulting in hyperexcitability and repetitive firing
- Repetitive firing → prolonged endplate potential and repetitive potential discharge in skeletal muscle fibres
What drugs can you use to treat neuromytonia? (2 examples)
Anti-convulsants (e.g. carbamazepine, phenytoin) which block voltage-activated Na+ channels
What are symptoms of Lambert-Eaton Myasthenic Syndrome (LEMS)?
-Muscle weakness in the limbs (may transiently improve upon exertion)
How common is LEMS?
-Very rare, associated with small cell carcinoma of the lung
What occurs in LEMS?
-Commonly autoimmune
-Antibodies against voltage activated Ca2+ channels in the motor neuron terminal result in reduced Ca2+ entry in response to depolarisation → reduced ACh release
What drugs can you use to treat LEMS? Example
-Anticholinesterases (e.g. pyridostigmine) which increases duration of ACh in the synaptic cleft and potassium channel blockers (e.g. 3,4-diaminopyridine) which increase the release of ACh by prolonging the action potential in the motoneurone terminal
What are symptoms of Myasthenia Gravis (MG)?
-Progressively increasing muscle weakness during periods of activity (fatiguability)
What occurs in MG?
-Commonly autoimmune
-Antibodies against nAChr in the endplate results in reduction in the number of functional channels → amplitude of endplate potential decreases
What drugs can you use to treat MG? Examples
-Anticholinesterases (e.g. pyridostigmine) which increase the concentration of ACh in the synaptic cleft
-Immunosuppressant agents (e.g. azathioprine)
What is botulinum toxin and where does it act?
An extremely potent exotoxin that acts at motor neurone terminals to irreversibly inhibit ACh release leading to muscle weakness or paralysis
How does the botulinum toxin inhibit ACh release?
Enters presynaptic terminals to enzymatically modify proteins involved in the docking of vesicles containing ACh to the presynaptic membrane, which prevents exocytosis
What can the botulinum toxin cause? How can it be used positively?
- Botulism (high death rate, recovery takes weeks as anti-cholinesterases are ineffective as therapy)
- Low dose botulinum haemaglutin complex can be administered IM to treat overactive muscles (dystonias) and also ‘botox’ for wrinkles
What are ‘curare-like’ compounds? What can they be used for clinically?
Act as competitive antagonists of nAChr so interfere with the postsynaptic action of ACh
- Endplate potential will be reduced to below the muscle fibre threshold potential
- Used clinically to induce reversible muscle paralysis in certain types of surgery (vecuronium, atracurium)
