Action Potential And Neuromuscular Junction

Question 1

What is the difference in the basic structure of a voltage gated Na+ and K+ channel?

Answer 1

• Each voltage gated potassium ion channel is made up of 4 individual alpha subunits
• Potassium channels don’t have inactivation particles
• Sodium channels are made from an alpha subunit split into 4 repeats.

13-15

Question 2

What is the difference between unprotonated and protonated?

Answer 2

Protonated is charged and unprotonated is not charged.

Unprotonated is membrane permeable

Pg 17-18

Question 3

Why is it important that Na+ Channels become inactivated?

Answer 3

• It is important the sodium channels become inactivated to enable the rapid switch off of the AP to enable the repolarisation to occur quickly.
• Also because the sodium channels are inactivated they cannot open again until they recover from inactivation and this leads to the refractory period which have important consequences for enabling the AP to move in the forward direction only.

Question 4

What is the consequence of delayed closing of voltage gated potassium channels?

Answer 4

Ensures that the hyperpolarisation of the AP reaches a fairly negative value and this will help with recovery of the inactivation of the sodium channels. The more hyperpolarisation you have the quicker the sodium channels will recover from inactivation.

Question 5

How are ion channels distributed in myelinated and unmyelinated axons?

Answer 5

• Ion channels of myelinated nerves are focused on the node of ranvier.
• Unmyelinated is equal distributed

Pg 32-33

Question 6

How does myelin sheath improve conduction?

Answer 6

Myelin sheath improves conduction by:

• large increase in membrane resistance (R m)
• large decrease in membrane capacitance (C m)
• these increase length constant (l)
• slight decrease in time constant (tm)

Question 7

What are different disease states affecting conduction of action potential?

Answer 7

CNS

• Multiple sclerosis - all CNS nerves
• Devic’s disease - optic and spinal cord nerves

PNS
• Landry-Guillain-Barre syndrome
• Charcot-Marie-Tooth disease

These diseases result from breakdown or damage to the myelin sheath. Multiple sclerosis is the most common demyelinating disease.

Question 8

What is action potential generation?

Answer 8

1. depolarisation to threshold triggers the opening of many voltage-gated Na+ channels.
2. Na+ influx produces the upstroke of the action potential (membrane potential moves towards E Na).
3. This depolarization causes inactivation of Na+ channels and opening of voltage-gated K+ channels.
4. Na+ influx stops and K+ efflux leads to repolarization (membrane potential moves towards E K).
5. Relatively little ions move and the Na/K ATPase is NOT involved in action potential repolarization

Question 9

What is action potential propagation?

Answer 9

1. an action potential causes local current flow leading to an immediate depolarization of adjacent
   sections of the axon
2. Where this local depolarization reaches threshold an action potential is initiated.
3. The spread of this local change in the membrane potential is increased by a high membrane
   resistance and low membrane capacitance – the longer this distance the faster the conduction.
4. myelinated axons have a high membrane resistance and low membrane capacitance.
5. At nodes of Ranvier, between the myelin sheaths, the axon is bare and the membrane has a high
   concentration of Na+ channels.
6. The action potential jumps from node to node – termed saltatory conduction, which is faster than
   that in unmeylinated axons.
7. Damage to the myelin (e.g. in multiple sclerosis) can stop saltatory conduction.

Question 10

What is the neuromuscular junction?

Answer 10

The synapse between a nerve and a skeletal muscle fibre.

Question 11

What are the different ion channels in the nerve terminal?

Answer 11

Voltage gated -

Sodium ion channels

Potassium ion channels

Calcium ion channels - this is important for the release of neurotransmitters.

Pg 42

Question 12

What happens at the nerve terminal? And what increases nerve terminal Ca2+ entry?

Answer 12

1. Action potential
2. Opens voltage gated calcium channels
3. Calcium entry/influx
4. Increased intracellular calcium ion concentration
5. Release of neurotransmitters.
   - The calcium intracellular is very low, so an influx will cause a raise in the internal concentration.
   - Also increase in the action potentials ill increase the amount of nerve terminal calcium entry

Pg 43-44

Question 13

What is the structure of the calcium channel?

Answer 13

• Similar to voltage gate sodium channels
• Alpha subunit with 4 repeats
• No inactivation particle
• S4 has positive charged amino acids and detects the change in membrane potential and causes a conformational change of the calcium ion.

Pg 45

Question 14

What is the subunit composition of Na+ and Ca+ channels?

Answer 14

• A pore forming alpha subunit is necessary for a functional channel.
• on the cytoplasmic face there are phosphorylation sites that can modify the activity of the channel
• On the extracellular fluid face side there are glycosylation sites.

Pg 46

Question 15

Describe the different components of the neuromuscular junction?

Answer 15

Pg 49

Question 16

How are transmitters released?

Answer 16

1. Ca2+ entry through Ca2+ channels.
2. Increased concentration of Ca2+ leads to the Ca2+ binding to synaptotagmin.
3. This brings the vesicle close to the membrane
4. When the vesicle comes into contact with the membrane the snare complex forms a fusion pore
5. This opens and allows transmitter release through the pore.

Pg 50-51

Question 17

How is the depolarisation in the skeletal muscle triggered?

Answer 17

1. Once released from the vesicle and passed through synapse, 2 molecules of ACh binds to the nAChR on the skeletal muscle.
2. This causes the pore of the nAChR to open and Na+ and K+ enters into the in the skeletal muscle

Question 18

How does depolarisation occur in the skeletal muscle?

Answer 18

• Depolarisation can occur because the resting membrane potential of skeletal muscle is very negative and close to the potassium equilibrium potential and further from the sodium one.
• So there is much more electrochemical gradient for sodium to move into the cell and for potassium to move out of the cell.
• This is why when Ach binds to its receptors there is a depolarisation of the muscle membrane and this is called the end plate potential.
• The depolarisation will try to reach a value half way between the sodium and potassium equilibrium potential, so about -10 mV and this is called the reversal potential of the channel.
• This is why you get a depolarisation from rest potential at about -90mV.

Pg 52

Question 19

What does end plate potential do and what can affect it?

Answer 19

• The end plate potential will raise the muscle membrane potential to threshold and this will initiate an AP in the skeletal muscle.
• Decrease of extracellular calcium concentration will lead to a reduction in the amplitude of the end plate potential .
• This is because you are decreasing the amount of calcium ions that can enter into the cell and release the transmitter.

Pg 53

Question 20

What does the muscle action potential do?

Answer 20

• The muscle action potential is initiated adjacent to the end plate and propagates along the muscle fibre
• The AP then initiated contraction of the skeletal muscle fibre - excitation contraction coupling.
• A single AP will cause a twitch
• A group AP will cause a strong contraction

Pg 54

Question 21

What does curare do?

Answer 21

• Causes paralysis by blocking the transmission between the nerve and muscle.
• it is ok to eat curare

Question 22

What are the 2 different types of nicotinic ACh receptor blockers?

Answer 22

Competitive blocker - binds to receptor and keeps it closed (reversible)

• Depolarising blocker - binds to the receptor and opens it but causes the inactivation of the Na+ channels.

Pg 56

Question 23

What is d-tubocurarine and what type of blocker is it ?

Answer 23

• It is the active component of curare and is a competitive blocker.
  1. Curare will bind at the ACh binding site, the nAChR will no longer open and you get a much smaller end plate potential.
  2. It is called competitive because the Ach has to compete with the curare to bind to the binding site, so if you increase the concentration of Ach you can overcome the block by the curare.
  3. The concentration of the Ach and the curare will determine wihether the nAChR will be open or closed.

Question 24

What type of blocker is succinylcholine and what does it do?

Answer 24

1. Succinylcholine will continually activate the, nAChR by binding to it, succinylcholine is able to open the receptors
   - Not very well broken down by acetylcholine esterase.
2. So this leads to a maintained depolarisation of the end plate potential, that’s why it’s called the depolarising blocker.
3. However the maintained depolarisation will fail to activate the Na+ channels because they have become inactivated.

Question 25

What is the use of neuromuscular blocking agents in operations?

Answer 25

• they are used in combination with general anaesthetics to cause temporary paralysis during surgery, muscles because relaxed and makes surgery easier.
• A person paralyzed with a neuromuscular blocker looks similar to a person under general anaesthesia, but unable to move or speak

Question 26

What is myasthenia gravis?

Answer 26

An autoimmune disease targeting nACh receptors.

• Patients may suffer profound weakness
• Weakness increases with exercise
• Caused by antibodies directed against nAChR on postsynaptic membrane of skeletal muscle.
• Antibodies lead to loss of functional nAChR by complement mediated lysis and receptor degredation.
• Endplate potentials are reduced in amplitude leading to muscle weakness and fatigue

Pg 60

Question 27

What is used to diagnose myasthenia gravis?

Answer 27

• The edrophonium test

Pg 61 - read it

Question 28

What is organophosphate and what is organophosphate poisoning?

Answer 28

• Organophosphates are used as insecticides (eg parathion, dimethoate).
• Are often a cause of accidental or self-inflicted poisoning.
• The more powerful ones have been developed as nerve agents used in war or terrorism (eg sarin,
  Novichok).

Mechanism of action:
• Acetylcholinesterase inhibitors that form a stable irreversible covalent bond to the enzyme.

• Recovery from poisoning may take weeks as synthesis of new acetylcholinesterase enzymes
is needed.

Question 29

What does ACh also bind to? And what is the difference between the two receptors?

Answer 29

muscarinic ACh receptor

• nAChR produces fast depolarisations because it is a ligand gated ion channel
• mAChR produce slower response because they are are coupled to G-proteins which trigger a cascade of events in the cell

Pg 63-64