Physiology and pharmacology of the skeletal neuromuscular junction - neuro wk 3 deck better

Question 1

What are the key features of the structure of the neuromuscular junction ?

Answer 1

• (1) the terminal bouton (and surrounding Schwann cell)
• (2) synaptic vesicles
• (3) the synaptic cleft
• (4) the end plate region of the muscle cell membrane (sarcolemma) thrown into a series of junctional folds

Question 2

Give an overview of neuromuscular transmission

Answer 2

1. Ach is synthesised from choline and acetyl coenzyme A (by the enzyme choline acetyltransferase)
2. Then stored in synaptic vesicles
3. Arrival of AP causes depolarisation resulting in Ca2+ channels opening and Ca2+ entering the terminal, Ach released
4. ACh activates nicotinic ACh receptors located at the muscle end plate, causing the receptors/channel to open
5. Na+ enters the muscle cell (influx) whist K+ exits (efflux) depolarization known as the end plate potential (e.p.p.) is generated

Question 3

What is the transmitter and the receptors in chemical transmission at the neuromuscular junction ?

Answer 3

Transmitter - ACh

Receptors - nicotinic ACh receptors

Question 4

How does the activation of nicotinic ACh receptors result in the generation of the end plate potential (e.p.p.)?

Answer 4

1. When ACh activates the nicotinic ACh receptors it results in the receptors/channels opening.
2. Na+ enters the muscle cell (influx) whist K+ exits (efflux)
3. Because the influx of Na+ is greater than efflux of K+: a depolarization known as the end plate potential (e.p.p.) is generated

Question 5

Describe the concept of miniature endplate potential (m.e.p.p) which summate to form end-plate potential (e.p.p) and how this ends up initiating contraction ?

Answer 5

1. ACh is stored in vesicles
2. Each vesicle contains a ‘quantum’ of neurotransmitter
3. One quantum of neurotrasmitter results in a miniature endplate potential (m.e.p.p) when released
4. Many m.e.p.ps summate to produce the end-plate potential (e.p.p)
5. An e.p.p that exceeds threshold triggers an ‘all or none’ propagated action potential that initiates contraction

Question 6

Why is the muscle action potential required for muscle contraction ?

Answer 6

The e.p.p., if large enough, triggers the opening of voltage-activated Na+ channels around the end plate causing an AP (muscle AP)

This is required because:

• Explained in pic
• Note different receptors/channels mediate the muscle AP from the e.p.p.

Question 7

How does the muscle AP result in muscle contraction ?

Answer 7

1. The muscle AP (note this is completely different from the e.p.p. although it was initated by it) propagates over the surface membrane (sarcolemma) of skeletal muscle fibre and enters transverse (T) tubules.
2. This results in Ca2+ released from sarcoplasmic recticulum.
3. Ca2+ interacts with troponin associated with myofibrils which results in muscle contraction

Question 8

How is neuromuscular transmission terminated and what by ?

Answer 8

Terminated by acetylcholinesterase

Rapid termination of neuromuscular transmission is the result of hydrolysis of ACh be acetylcholinesterase (AChE)

Question 9

What is Neuromyotonia (NMT, or Isaac’s syndrome)?

Answer 9

Condition due to antibodies against voltage-activated K+ channels in the motor neurone disrupt function resulting in hyperexcitability (repetitive firing)

Symptoms include multiple disorders of skeletal muscle function including cramps, stiffness, slow relaxation (myotonia), and muscle twitches (fasiculations)

Question 10

What is the treatment of Neuromyotonia (NMT, or Isaac’s syndrome)?

Answer 10

Anti-convulsants (e.g. carbamazepine, phenytoin) which block voltage-activated Na+ channels

Question 11

What is Lambert-Eaton Myasthenic Syndrome (LEMS)?

Answer 11

• Characterised by muscle weakness in the limbs, very rare and associated with small cell carcinoma of the lung
• Antibodies against voltage-activated Ca2+ channels in the motor neurone terminal result in reduced Ca2+ entry in response to depolarization and hence reduced vesicular release of ACh

Question 12

What is the treatment of Lambert-Eaton Myasthenic Syndrome (LEMS)?

Answer 12

Anticholinesterases (e.g. pyridostigmine) and potassium channel blockers (e.g. 3,4-diaminopyridine) which increase the concentration of ACh in the synaptic cleft

Question 13

What is Myasthenia Gravis (MG)?

Answer 13

Characterised by progressively increasing muscle weakness during periods of activity (fatiguability, contrast with LEMS that may transiently improve upon exertion). Often weakness of the eye and eyelid muscles is a presenting feature

Antibodies against nicotinic ACh receptors in the endplate result in reduction in the number of functional channels and hence the amplitude of the e.p.p.

Question 14

What is the treatment of mysantheia gravis ?

Answer 14

Drug treatment includes anticholinesterases (e.g. edrophonium for diagnosis, pyridostigmine for long term treatment) and a variety of immunosuppressant agents (e.g. azathioprine).