Skeletal muscle 1: Neuromuscular transmission

Question 1

What are the basic units of skeletal muscles?

Answer 1

1. Neuromuscular junction (NMJ)
2. Cellular machinery (proteins and subcellular structures)
   involved in excitation-contraction coupling
3. Sarcomeres containing the contractile apparatus

Question 2

What is a motor unit?

Answer 2

A single alpha motor neuron and the muscle fibres it innervates

Question 3

What are the two classifications of motor units?

Answer 3

Type 1 (slow) and Type 2 (Fast)

Question 4

What is the size principle?

Answer 4

When recruiting muscle fibres, the small oxidative motor units are recruited first (they have a lower threshold) follow by the large glycolytic motor units. There are more small fibres compared to large fibres

Question 5

Explain what happens at the NMJ

Answer 5

At the NMJ, the motor axon loses its myelin sheath and branches which each make synaptic contact with a muscle fibre.
The motor end-plate membrane of the folds contain two distinct domains.
At the crests (muscle motor end-plate), there is a high concentration of Acetylcholine Receptors (AChRs), and the AChR-clustering proteins Rapsyn and Utrophin.
In the depth of the folds, there is a high concentration of Voltage-gated sodium channels (VGSCs)

Question 6

What are the pre-synaptic events?

see page 80 for diagram

Answer 6

1. An action potential (AP) in the pre-synaptic cell reaches the nerve terminal
2. Depolarisation of the terminal opens voltage-gated Ca2+ channels, resulting in Ca2+ influx
3. Increase in [Ca2+] leads to exocytosis of vesicles containing ACh
4. ACh diffuses across the synaptic cleft and binds to ACh receptors
5. ACh is broken down by acetylcholinesterase in the synaptic cleft

Question 7

What are the post-synaptic events?

see page 81 for diagram

Answer 7

1. At the motor end-plate on the muscle fibre, end-plate current (EPC) is generated by the opening of AChR-ion channels.
2. A lot more Na+ ions enter and fewer K+ ions leave, producing a net inward, depolarising current
3. The channels close as ACh unbind and is removed from the synaptic cleft by acetylcholinesterase
4. The falling time course of EPC is determined by the random closure of individual channels that are open for a range of times

Question 8

What is the end-plate potential (EPP)?

Answer 8

1. EPPs are always suprathreshold and will trigger an AP in the muscle fibre
2. The EPP travels for a short distance within the cell before dissipating
3. The EPC and EPP have different time courses
4. EPC has a time course defined by the mean open time of the AChR channels
5. EPP has a longer time course defined by both AChR channel open time and passive electrical discharging time of muscle membrane

Question 9

What is the sequence of events in neuromuscular transmission?

Answer 9

AP in presynaptic cell reach nerve terminal –> depolarisation of nerve terminal opens voltage-gated Ca2+ channels –> increased [Ca2+] triggers exocytosis of vesicles and quantal release of ACh –> binding of 2 ACh molecules to each post-synaptic transmitter-gated channel –> Channel opens –> influx of Na+ (and Ca2+) and efflux of K+ –> Depolarisation of motor end-plate (EPP) –> Opening of VGSC –> Na+ influx –> Propagated AP in muscle fibre

Question 10

Explain Myasthenia Gravis (MG)

Answer 10

MG is an autoimmune disorder in which antibodies against the AChR are produced. These antibodies bind and reduce the number of functional receptors, inhibiting AP initiation. Muscles controlling the eyelids, facial expression and swallowing are usually affected.

Can be treated with anti-acetylcholinesterase/immunosuppressive drugs