Physiology of the Neuromuscular Junction Flashcards
What type of movement does skeletal muscle mediate
Voluntary movement
What innervated skeletal muscles
Motor neurones with myelinated axons and cell bodies in the spinal cord or brain stem
Each unmyelinated branch of a motor neurone axon innervates how many skeletal muscle cells within a muscle
One
What is a motor unit
The neurone and the number of fibres that it innervates
What forms a chemical synapse with the muscle membrane at the neuromuscular junction
Individual branches which have further divided into multiple fine branches, each ending in a terminal bouton
What causes the release of the neurotransmitter acetylcholine?
Action potentials that arise in the cell body conduct via the axon to the boutons causing the release
Where does the presynaptic terminal (bouton) synapse at?
The endplate region of skeletal muscle fibres
What are the 4 key features of the skeletal Neuromuscular junction
- the terminal bouton (and surrounding Schwann cell
- synaptic vesicles
- the synaptic cleft
- the end palte region of the muscle cell membrane (sarcolemma)
Where are nicotinic ACh receptors located
At regions of the junctional folds that face the active zones
What is contained in the synaptic vesicles
A high concentration of ACh
How large is the synaptic cleft
Very narrow
Describe the 5 steps involved in the synaptic transmission at the skeletal neuromuscular junction
- synthesis of Neurotransmitter
- Storage of neurotransmitter
- release of Neurotransmitter under control of Ca+
- Receptor activation
- Transmitter inactivation - mediated by Ach esterase
How is choline transported into the terminal
By the choline transporter - this requires energy
What concentrates ACh in the vesicles
The vesicular ACh transporter
What happens when the Action Potential arrives at the terminal
Causes depolarisation and the opening of voltage activated Ca2+ channels. This allows Ca2+ entry to the terminal
What does Ca2+ cause the vesicles to do
Fuse with the presynaptic membrane
This allows ACh to diffuse into the synaptic cleft to activate post synaptic nicotinic ACh receptors in the endplate region
In the post synaptic process, what does ACh activate
Nicotinic ACh receptors located at the muscle end plate
How are Nicotinic ACh receptors assembled
As a pentamer of glycoprotein subunits that surround a central, cation selective pore. (5 M2 helicesmake this pore)
What does the pore contain
A gate that is closed in the absence of ACh but open when two molecules of ACh bind to the exterior of the receptor
What happens when the gate is open
Na enters the muscle cell whilst K exits simultaneously through many receptors at the end plate
Why is influx of Na greater than the efflux of K+
Because of the driving force for Na being greater than that for K+ at resting membrane
What causes the generation of the end plate potential
The depolarisation due to the greater influx of Na compared to that of the efflux of K+
What is a miniature endplate potential
The electrical response to one quantum of transmitter, due to the activation of nicotinic ACh receptors at the endplate
How is a contraction initiated
When an end-plate potential exceeds threshold triggers and an all or none propogated action potential will initiate contraction
What type of response is the EPP
A graded response
What causes a twitch of the muscle
Normally one action potential in the motor nerve triggers one action potential in the muscle (one to one coupling)
Describe the way in which action potentials spread in skeletal muscle
They are regenerative - as soon as 1 opens, adjacent ones are reached and rapid interaction occurs
What happens when an action potential arrives at the T tubule
It triggers release of Ca2+ from the SR which in turn causes contraction by interacting with troponin associated with the myofibrils
What is the result of hydrolysis of ACh by acetylcholinesterase
Rapid termination of the neuromuscular transmission
What happens to the acetate when ACh is hydrolysed
It diffuses from the synaptic cleft
What is an important target of some therapeutic agents and also some insecticides and nerve gases used in warfare
Aceytlcholinesterase
What are some of the symptoms of Neuromyotonia (Isaac’s syndrome)
Multiple disorders of skeletal muscle function including cramps, stiffness, slow relaxation and muscle twitches
What is the drug treatment for Neuromyotonia
Anti-convulsants (carbamazepine, phenytoin) which block voltage activated Na+ channels
What is Lamber-Eaton Myasthenic Sydrome characterised by
Muscle weakness in the limbs, very rare and associated with small cell carcinoma of the lung
What is the origin of LEMS
Autoimmune - antibodies against voltage activated Ca2+ channels in the motor neurone terminal result in reduced Ca2+ entry in response to depolarisation and hence reduced vesicular released of ACh
WHat is the drug treatment for LEMS
Anticholinesterases (pyridostigmine) and potassium channel blockers which increase the concentration of ACh in the synaptic cleft
What is Myasthenia Gravis characterised by
Progressively increasing muscle weakness during periods of activity
Often weakness of the eye and eyelid muscles is a presenting feature
What is the drug treatment for Myasthenia Gravis
Anticholinesterased (edrophonium for diagnosis and pyridostigmine for treatment)
Also use an immunosuppressant agent (azathioprine)
What is Botulinum Toxin
An extremely potent exotoxin toxin (related to tetanus and diptheria toxins) that act at motor neurone terminals to rreversibly inhibit ACh release
What does Botulinum Toxin do when it enters the presynaptic nerve terminal?
Enzymatically mofidies proteins involved in the docking of vesicles containing ACh
What is the death rate like in Botulinum Toxin
High - recovery takes several weeks - drugs that block acetylcholinesterase are ineffective as therapy
How is botulinum haemaglutin complex administered
By intramuscular injection to treat overactive muscles (e.g. extraocular muscles)
What do curare-like compounds do?
They Interfere with the postsynaptic action of acetylcholine by acting as competitive antagonists of the nicotinic ACh receptor
Reduce the amplitude of the endplate potential to below the threshold for muscle fibre action potential generation
Why are curare-like compounds used clinically
to induce reversible muscle paralysis in certain types of surgery
