1.9B. Neuromuscular junction and physiology of the skeletal muscle.

Question 1

I. The neuromuscular junction
1. What is the neuromuscular junction?

Answer 1

The neuromuscular junction (or motor end plate) is a chemical synapse between a neuron and a muscle.

Question 2

II. The neuromuscular transmission
1. What is the general mechanism of neuromuscular transmission?

Answer 2

1/ ACh is released by an α-motorneuron into the synaptic cleft between the axon terminal and the skeletal muscle membrane (sarcolemma).

2/ The released ACh binds to a receptor on the sarcolemma to induce an AP. (ACh is the only NT of the NMJ!)

Question 3

II. The neuromuscular transmission
2. What is the 9-step process of neuromuscular transmission?

Answer 3

1. An AP traveling down the axon of the alpha-motor neuron reaches the axon terminal, leading to membrane depolarization
2. As a result of the depolarization, the VG Ca2+-channels open -> Ca2+-influx
3. Exocytosis of synaptic vesicles containing ACh
   -> ACh released into the synaptic cleft
4. ACh diffuses across the synaptic cleft and binds to nAChR (ligand-gated non-specific cation channel) on the postsynaptic membrane (motor end plate)
5. nAChRs undergo a conformational change, increasing their permeability to both Na+ and K+. Na+ flows in, K+ flows out -> depolarization of membrane from resting Em of
   -90mV to threshold potential of 50mV (end plate potential, EPP)
6. Depolarization of the end plate spreads via local currents to adjacent parts of the muscle fiber
7. The propagation of the electrotonic potential leads to
   -> Activation of the VG Na+-channels -> AP initiated upon summation
8. AP propagates through the T-tubules and the sarcolemma
9. Degradation of ACh by ACh-esterase into choline and acetate
   -> Acetate diffuses away, choline re-enters cellinduce an AP. (ACh is the only NT of the NMJ!)

Question 4

III. ACh synthesis and recycling
1. What is the 3-step process of ACh synthesis?

Answer 4

1. ACh is synthesized from choline and acetyl CoA by choline acetyl-transferase in the axon terminal
2. ACh is transported into the synaptic vesicle by ACh-H+ exchanger (secondary active transport)
3. The antiporter carries H+ out and ACh into the vesicles

Question 5

III. ACh synthesis and recycling
1. What is the 3-step process of ACh synthesis?

Answer 5

1. ACh is synthesized from choline and acetyl CoA by choline acetyl-transferase in the axon terminal
2. ACh is transported into the synaptic vesicle by ACh-H+ exchanger (secondary active transport)
3. The antiporter carries H+ out and ACh into the vesicles

Question 6

III. ACh synthesis and recycling
2. What is the 2-step process of ACh recycling?

Answer 6

1. After the exocytosis of the synaptic vesicles, ACh is broken down to choline and acetate by ACh-esterase
2. Uptake of choline by the nerve cell through Na+-choline cotransporter (secondary active transport)

Question 7

IV. Pharmacology of neuromuscular junction
1B. What are muscle relaxants?

Answer 7

Muscle relaxants: modulates muscles to relieve pain (muscle relaxation)

Question 8

IV. Pharmacology of neuromuscular junction
1C. What are the examples of external toxins (aka, muscle relaxants)? What are their characteristics?

Answer 8

1/ Depolarizing (agonists of nAChR - inactivation of Na+ channels)
- Succinylcholine
- Carbachol

2/ Non-depolarizing (inhibitors of nAChR)
- Curare
- Tubocurare
- Pancuronium

Question 9

IV. Pharmacology of neuromuscular junction
1D. Characteristics of Depolarizing (agonists of nAChR - inactivation of Na+ channels)

Answer 9

• Persistent depolarization makes the muscle fiber resistant to further stimulation of ACh

Question 10

IV. Pharmacology of neuromuscular junction
1E. Characteristics of Curare

Answer 10

• Non-depolarizing (inhibitors of nAChR)
• Competitive antagonist
• Compete with ACh for receptor, leading to end-plate potential (EPP) decrease

Question 11

IV. Pharmacology of neuromuscular junction
1E. Characteristics of Tubocurarine

Answer 11

• Relax skeletal muscle -> anesthesia

Question 12

IV. Pharmacology of neuromuscular junction
1F. Characteristics of Succinylcholine

Answer 12

• Depolarizing
• A partial agonist

Question 13

IV. Pharmacology of neuromuscular junction
2A. What is Myasthenia gravis?

Answer 13

An Autoimmune disease that has auto-antibodies against nAChR

Question 14

IV. Pharmacology of neuromuscular junction
2B. What are some treatments for Myasthenia gravis?

Answer 14

• Neostigmine: inhibits the breakdown of ACh when it is released from nerve endings. This means that there is more ACh available to attach to the muscle receptors and will improve the muscle strength
• in larger doses: twitches + spasms first and then paralysis