Session 4

Question 0

Draw the Action Potential of An Axon including duration

Answer 0

Question 1

What are the properties of an action potential?

Answer 1

An AP is a change in voltage across a membrane

Depends on ionic gradients and relative permeability of the membrane

Only occurs if a threshold level is reached

All or nothing - all action potentials are the same

Propagated (conducted along the axon) without loss of amplitude

Question 2

Draw the Action Potential of Skeletal Muscle including duration

Answer 2

Question 3

Draw the Action Potential of a Sinoatrial Node including duration

Answer 3

Question 4

Draw the Action Potential of a Cardiac Ventricle including duration

Answer 4

Question 5

What is the Sodium Hypothesis?

Answer 5

Influx of Na+ ions drives the rise (upward stroke) of the action potential in axons; APs are generated by an increase in permeability to Na+ bringing the membrane potential closer to the E(Na).

Once the membrane has been depolarised to the threshold voltage,

Positive Feedback occurs as Na+ channels open allowing Na+ influx as Na+ ions attempt to move to their equilibrium potential of +61mV

Influx depolarises the membrane further, causing more voltage-gated Na+ channels to open and even more depolarisation.

Question 6

Describe what is happening during Repolarization (downstroke of action potential)

Answer 6

During maintained depolarisation, Na+ channels are closed by a mechanism called inactivation.

Voltage gated K+ channels are also opened (activated) by depolarisation causing a K+ ion efflux as K+ attempts to move towards it’s own equilibrium potential.

A combination of these two events causes the membrane to repolarise. NOTE THAT Sodium Pump is not involved in the repolarization of the action potential.

Question 7

Describe the change in ion concentration gradient needed for generating an action potential

Answer 7

SMALL Change in concentration = mol/volume

Question 8

What are the ways of investigating the mechanism of Action Potential generation?

Answer 8

Voltage-clamping controls the membrane potential - allows measurement of ionic (membrane) currents at a constant voltage (set membrane potential)

Using different ionic concentrations the contribution of various ions can be assessed,

Patch-clamping enables currents flowing through individual ion channels to be measured.

Question 9

Where is the action potential initiated?

Answer 9

Depolarization to threshold initiates an action potential at the axon hillock

Question 10

Describe the All or Nothing basis of an AP

Answer 10

The Na+ channels that open to cause depolarisation are voltage-gated.

This means that as the membrane potential becomes more positive, positive feedback means that more channels will open until they all are.

The depolarisation cannot stop halfway as this voltage will be the point at which more channels open, thus causing more depolarisation.

Question 11

What happens to the Na+ channels after an action potential has been generated?

Answer 11

Most of the Na+ channels have been inactivated - as soon as Na+ channels are open they are susceptible to becoming inactivated very rapidly.

Na+ channels only recover during Hyperpolarization (become closed).

Question 12

What is the ARP?

Answer 12

Absolute Refractory Period

Nearly all Na+ channels are in the inactivated state. The period is the duration of the action potential

Excitability is 0 - not able to generate an Action Potential (Excitability 1= cell is ready to generate an AP)

Question 13

What is the RRP?

Answer 13

Relative Refractory Period

Na+ channels are recovering from inactivation. The excitability returns towards normal as the number of channels in the inactivated state decreases

A stronger stimulus is needed to generate an AP (threshold potential is likely to be positive at this point)

Question 14

What is accommodation?

Answer 14

The longer the stimulus, the larger the depolarization necessary to initiate an action potential - the threshold becomes more positive due to the accumulation of inactivated sodium channels which can only recover during Hyperpolarization.

Stimuli of slowly increasing intensity causes the threshold potential to become more positive until the threshold is no longer reached as too many Na+ channels are inactivated so an AP can’t be generated - even if membrane potential surpasses the original threshold.

Question 15

Describe the basic structure of voltage gated Na+ and Ca2+ channels

Answer 15

They are similar in structure.

Their main pore-forming alpha subunit is one peptide consisting of 4 homologous repeats.

Each repeat consists of 6 transmembrane spanning domains with one of those domains being voltage-sensitive (able to detect the voltage field across the membrane)

A functional channel requires 1 subunit.

There is also an inactivation particle attached to the subunit - ‘ball polypeptide’ - acts as a plug, entering the pore and binds, preventing flow of ions.

Question 16

Describe the structure of voltage gated K+ channels.

Answer 16

Similar in structure to Na+ but EACH REPEAT is a SEPARATE SUBUNIT.

Each subunit still has six transmembrane domains, one of which is voltage sensitive

A functional channel requires 4 alpha SUBUNITS.

The S4 region on each subunit has positive amino acid residues which sits within the membrane so when the voltage changes, it undergoes a conformational change leading to opening or closing of the the ion channel. The P (or H5) region contributes to pore selectivity.

Question 17

Describe the action of local anaesthetics

Answer 17

Local anaesthetics such as Procaine act mainly by binding to and blocking Na+ channels, thereby stopping AP generation.

They block conduction in nerve fibres in the following order:

1. Small myelinated axons
2. Non-myelinated axons
3. Large myelinated axons Because of this they tend to effect sensory before motor neurons.

Question 18

Describe the properties of local anaesthetics

Answer 18

They are weak bases and cross the membrane in their unionised form.

They block Na+ channels when the channel is open and also have a higher affinity to the inactivated state of the Na+ channel - the more Na+ channels are open, the more they are blocked.

Question 19

Describe Extracellular Recording and how can it be used to measure Conduction Velocity?

Answer 19

Different classes of axons have different sized diameters and different conduction velocities.

Electrical stimulation: electrodes are used to raise the membrane potential to threshold to generate an action potential.

By recording changes in between the stimulating cathode (-ve) and recording anode (+ve) electrodes along an axon, conduction velocity can be calculated using the equation conduction velocity = Distance / time

Question 20

How is the action potential calculated?

Answer 20

Measure the distance between the stimulating electrode and the recording electrode

Measure the time gap between the stimulus and the action potential being registered by the recording electrode.

Conduction Velocity = Distance / Time

Question 21

Explain the Local Current Theory of Propragation

Answer 21

Happens more or less instantaneously.

Injection of current (depolarisation) into the of the membrane of an axon will cause the resulting charge (influx of Na+) to spread along the axon and cause an immediate local change (depolarisation) in the membrane potential.

This is electrotonic/passive membrane potential spread but NOT AN ACTION POTENTIAL.

Question 22

How is an Action Potential conducted along an axon?

Answer 22

A change in membrane potential in one part can spread to adjacent areas of the axon because of local current spread.

The depolarisation of a small region of membrane produces transmembrane currents in neighbouring regions.

As Na+ channels are voltage gated, this opens more channels, causing the propragation of the action potential.

The further the local current spreads, the faster the conduction velocity of the axon.

Question 23

What are the properties that lead to a high conduction velocity?

Answer 23

A high membrane resistance

A low membrane capacitance

A large axon diameter (this leads to low cytoplasmic resistance)

Question 24

Explain how high membrane resistance leads to a high conduction velocity?

Answer 24

Ohm’s Law: V=IR, states that the higher the resistance of the membrane, the higher the potential difference across it.

More voltage across the membrane means more voltage gated Na+ channels are open; making it easier to reach the threshold to fire an AP. Conduction velocity is therefore increased.

Question 25

How does Large Axon Diameter increase Conduction Velocity?

Answer 25

Ohm’s Law: I = V / R states that the lower the resistance (in this case low cytoplasmic resistance is due to large axon diameter), the larger the current, therefore the action potential will travel further. Conduction velocity is therefore increased.

Question 26

How does low membrane capacitance lead to high conduction velocity?

Answer 26

Capacitance is the ability to store charge and is a property of the bilayer.

Therefore a membrane with a high capacitance takes more current to charge (or a longer time for a given current) and can cause a decrease in spread of the local current, especially with brief current pulses.

Similarly for a given current, a membrane with a low capacitance will take less time to charge, increasing conduction velocity.

Question 27

Describe the effect of myelination on conduction velocity?

Answer 27

Conduction velocity is increased considerably by myelination of axons.

Large diameter axon such as motoneurones are myelinated.

Smaller ones such as C-fibres (sensory neurones) are not.

Question 28

How does myelination increase conduction velocity?

Answer 28

Reduces capacitance

Increases membrane resistance of the axon

Question 29

How is myelin formed by special cells?

Answer 29

Schwann cells myelinate peripheral axons

Oligodendrocytes myelinate axons in the CNS

They both envelop axons in the plasmalemma.

Question 30

What is Saltatory Conduction?

Answer 30

Myelination allows for Saltatory conduction.

This is where the AP jumps between Nodes of Ranvier - allowing a faster conduction velocity.

Myelin changes the property of the membrane - acts as a good insulator, thereby causing the local circuit currents to depolarize the next node above the threshold and initiate an AP

An action potential occurs only at the nodes.

Question 31

Describe the distribution of Na+ channels on myelinated and unmyelinated axons

Answer 31

The Nodes of Ranvier have a higher density of voltage gated Na+ channels which is in contrast to unmyelinated axons which have an even distribution of Na+ channels along the axon.

Question 32

How much does myelin sheath improve conduction by?

Answer 32

Approx 100x increase in membrane resistance

Approx 100x decrease in membrane capacitance.

These increase the length constant.

Slight decrease in time constant (changes in membrane potential occur more quickly)

Conduction velocity increases.

Question 33

Describe the consequences of demyelination

Answer 33

In regions of demyelination, the density of the action current is reduced because of resistive and capacitive shunting so at the next node, there is a failure to reach threshold so an action potential is not generated.

Question 34

What happens in Multiple Sclerosis?

Answer 34

Autoimmune disease where antiobodies and WBCs attack myelin, causing inflammation and injury to the sheath until myelin is destroyed in certain areas of the CNS. This causes multiple plaque formation/ scarring so stop AP generation.

Loss of myelin leads to laekage of K+ through voltage-gated channels, hyperpolarization and failure to ocnduct action potentials.

Depending on the different locations this can happen, there can be different symptoms.

This can have dramatic effects on the ability of previously myelinated axons to conduct action potentials properly.

This can lead to decreased conduction velocity, complete block or cases where only some action potentials are transmitted.

Question 35

Explain how membrane resistance depends on number of open ion channels

Answer 35

The lower the resistance the more ion channels are open and the more loss of the local current occurs across the membrane, thus limiting the spread of the local current effect.

These local currents cause the action potential to propagate down the axon.

Increasing the conduction velocity increases the length constant (λ)

Open K+ channels decrease the resistance of the membrane – decreases length constant.

Question 36

Draw the relationship between conduction velocity and fibre diameter for myelinated and unmyelinated nerve fibres.

Answer 36

Question 37

When during development does myelination occur?

Answer 37

Schwann cells originate from the neural crest, migrate peripherally and wrap themselves around axons forming the myelin sheath.

Beginning at the fourth month of foetal life.

Some of the motor fibres in the spinal cord descending from higher brain centres do not become myelinated until the first year of postnatal life.

Tracts in the nervous system become myelinated at about the time they start to function.

Question 38

Are myelinated or unmyelinated nerve fibres easier to stimulate using stimulating electrodes, for example applying current to human peripheral nerves through the skin?

Answer 38

Myelinated because of high density of channels at a node of Ranvier so easier to stimulate - easier to depolarise.

Question 39

Some myelinated nerve fibres are able to regenerate from the central end if cut. Does this occur in the PNS or CNS? And what is the rate of such regeneration

Answer 39

• Occurs in the PNS
• The nerve begins the process by destroying the nerve distal to the site of injury, allowing Schwann cells, basal lamina and the neurilemma near the injury to begin producing a regeneration tube.
• When one of the growth processes finds the regeneration tube, it begins to growth towards its original destination guided the entire time by the regeneration tube.
• Nerve regeneration is very slow and can take up to several months to complete.
• While this process does repair some nerves, there will still be some functional deficit as the repairs are not perfect.

Question 40

How does Partial and Complete Demyelination affect Impulse Conduction

Answer 40

• Complete failure of conduction due to increased capacitance and current leak.
• Slower conduction as the sodium channels disperse from the nodes of Ranvier

Question 41

Will demyelination make nerve fibres easier or more difficult to stimulate with currents applied with stimulating electrodes?

Answer 41

Demyelination of a large finre: more membrane to stimulate (high capacitance) so more difficult to stimulate as you have to overcome this high capacitance.

In a myelinated fibre you have low capacitance at nodes of Ranview

Question 42

What might be the effect of treating a demyelinated nerve fibre with an agent that blocks voltage-gated Potassium Channels?

Answer 42

Becasue fast K+ channe;s may contribute to the repolarisation phase of an action potential, blocking of these K+ channels may prolong the spike (depolarisation) and facilitate its propagation through demyelinated region.

Clinical trials of these aminopyridines (K+ channel blockers) showed some symptomatic relief in patients with MS but the drugs have not yet proved effective enough for clinical use.