Synaptic Transmission

Question 1

What is a neuromuscular junction?

Answer 1

Synapse between a nerve and a skeletal muscle fibre.

Question 2

What is the main difference between a nerve terminal and the rest of the axon?

Answer 2

High density of voltage-gated calcium channels.

Question 3

Which ion channels are present in the nerve terminal?

Answer 3

• Voltage-gated Na+ channels
• Voltage-gated K+ channels
• Voltage-gated Ca2+ channels

Question 4

Describe the structure of voltage-gated calcium channels.

Answer 4

• Structure of alpha-subunit of VOCC is very similar to voltage-gated Na+ channel: 1 peptide with 4 voltage-sensing domains = functional pore-forming subunit.
• Other associated subunits fine tune the properties and enable correct regulation of channel activity.

Question 5

How can the activity of VOCC be regulated?

Answer 5

• Phosphorylation
• E.g. NA activates beta1 GPCR - Gs - AC - PKA pathway in cardiac ventricles leading to PKA phosphorylating VOOCs to increase calcium entry into myocytes for increase inotropy.

Question 6

Describe the process of calcium channel inactivation.

Answer 6

• VOCCs inactivate (and activate) more slowly than voltage-gated Na+ channels.
• VOCC inactivation is calcium-dependent: increased intracellular calcium leads to VOCC inactivation through:
  
  • direct binding of Ca2+ to the VOCC-calmodulin complex
  • Ca2+ mediated dephosphorylation of VOCC
  • Ca2+ dependent disruption of connection between VOCC and cytoskeleton

Question 7

Describe the process of NT release from the pre-synaptic membrane.

Answer 7

1. Nerve membrane depolarisation - calcium entry through VOCC.
2. Ca2+ binds to synaptotagmin (involved in synaptic vesicle docking and fusion).
3. NT vesicle brought closer to membrane - SNARE complex makes a fusion pore.
4. NT released through pore.

Question 8

How can the amount of NT released be increased?

Answer 8

• Increase frequency of APs - increases amount of nerve terminal Ca2+ entry - increases signal strength.

Question 9

Describe the generation of an AP by ACh.

Answer 9

1. ACh released from the pre-synaptic terminal diffuses across the synaptic cleft.
2. 2 ACh bind to nicotinic ACh receptor - conformational change in receptor - causes cation-selective pore opening.
3. Na+ enters cell, K+ exits cell through pore at equal rate.
4. Membrane depolarisation.
5. ACh degraded quickly by ACh esterase.

Question 10

Why is membrane depolarisation generated by the entry/exit of Na+/K+ through pore at equal rate?

Answer 10

• Membrane is already close to K+ equilibrium - driving force for K+ to exit is smaller than force for Na+ to enter.

Question 11

How does an AP generate muscle fibre contraction?

Answer 11

• Brief depolarisation initiated close to end plate activates adjacent Na+ channels due to local spread of charge - muscle AP.
• AP propagates along fibre and initiates contraction of skeletal muscle.

Question 12

How can muscle contraction by blocked?

Answer 12

• By blocking nicotinic ACh receptors - nerve cell cannot pass on electrical signal to muscle cell.

Question 13

What are the 2 main types of nAChR blockers?

Answer 13

1. Competitive blocker
   E.g. Tubocurarine - prevents ACh binding (although block by d-TC can be overcome by increasing ACh concentration).
2. Depolarising blocker
   E.g. Succinylcholine - binds and activates nAChR but maintains depolarisation state - initial contraction but will fail to activate adjacent Na+ channels as they will become inactivated.

Question 14

Name a disease involving nAChRs?

Answer 14

MYASTHENIA GRAVIS

Question 15

What is myasthenia gravis?

Answer 15

• Autoimmune disease where antibodies are directed against nAChR on post-synaptic membrane of skeletal muscle.
• Leads to loss of functional nAChR by complement-mediated lysis and receptor degradation.
• Endplate potentials are reduced in amplitude and fail to reach threshold - muscle weakness and fatigue.

Question 16

Compare the roles of nAChRs and mAChRs.

Answer 16

nAChR

• Ligand-gated R on skeletal muscle
• Produces fast depolarisation because it is ligand-gated ion channel.

mAChR

• GPCR on membrane of target tissue in parasympathetic autonomic nervous system.
• Produces slower response as is coupled to G proteins which trigger a cascade of events in the cell.