1.6. The development of the action potential in excitable cells: similarities and differences between distinct cells. Conduction of the action potential.

Question 1

I. Basics
1A. Definition of graded (electrotonic) potential?

Answer 1

A localized change in the membrane potential in response to a stimulus, which its size and duration proportional to the stimulus
- The distance over which the change in the potential decreases to a factor of 1/e of its maximal value is called the length or space constant

Question 2

I. Basics
1C. What are the definitions of depolarization, hyper polarization and repolarization?

Answer 2

1/ Depolarization -> bring the membrane potential closer to firing (more positive)
2/ Hyperpolarization -> brings the membrane potential less likely to depolarize (more negative)
3/ Repolarization -> restores the difference in charge between the inside and outside of the cell membrane following depolarization

Question 3

I. Basics
2A. What is the definition of AP?

Answer 3

a rapid, transient, self-propagating electrical excitation in the plasma membrane of an excitable cell (ex: nerve or muscle cells)

Question 4

I. Basics
2B. What are the characteristics of AP?

Answer 4

It is characterized by a rapid depolarization followed by repolarization to the resting membrane potential

Question 5

I. Basics
3. What the 3 ways that AP differ from other responses?

Answer 5

1) AP has a much larger amplitude
2) AP is generally propagated down the entire length of the axon without decrement (dying out)
3) AP is an ‘’all-or-none’’ response (becomes either a full-sized AP or fails to become one)

Question 6

I. Basics
4. Make a comparison between AP and graded potential

Answer 6

Question 7

I. Basics
5. What is the length/space constant?

Answer 7

Space or length constant is the distance over which the change in the potential decreases to a factor of 1/e of its maximal value

Question 8

II. Development of action potential
1. What is the General mechanism of AP development?

Answer 8

Generally, action potentials develop as the result of a graded (electrotonic) potential which reaches the threshold voltage and stimulates a coordinated sequence of opening and closing of voltage-gated ion channels
=> resulting in depolarization and repolarization

Question 9

II. Development of action potential
2. What are the characteristics of voltage-dependent Na+ channel? (threshold voltage, activation and inactivation)

Answer 9

1/ Ethr = -50 mV
2/ Rapid activation
3/ Inactivation

Question 10

II. Development of action potential
3. What are the characteristics of voltage-dependent K+ channel? (threshold voltage, activation and inactivation)

Answer 10

Voltage-dependent K+-channel (delayed = low activation)
1/ Ethr = -50 mV
2/ Slow activation
3/ No inactivation

Question 11

II. Development of action potential
4A. How does AP develop in neurons? (7 steps)

Answer 11

1) At rest,K+- permeability is high and Na+-permeability is low, leading to a membrane potential of -70mV

2) Influx of positive charges causes a depolarization to reach the threshold potential of -50mV, and trigger an action potential

3) When the AP is generated, Na+-ions rush into the neuron as the voltage-gated Na+ channels open, while the voltage-gated K+ channels remain closed

During the depolarization phase, the neuron cannot transmit another impulse whatsoever = absolute refractory period (voltage-gated Na+ channels are inactivated)

4) When the Na+-ions almost stop rushing into the neuron, the voltage-gated Na+ channels become inactivated

5) At the top of the spike (+35mV to +40mV), repolarization occurs (restoring the negative charge inside the neuron) due to 2 mechanisms:
- Slow inactivation gates close on the same VG Na+-channels with a delay
- Opening of the VG K+-channels
6) The VG K+ channels remain opened
-> Causes excessive flow of K+-ions out of the neuron = causes only negative potential inside (hyperpolarization / afterhyperpolarization / undershoot) to -87mV
7) It can fire a 2nd action potential, but a stronger stimulus than normal is required = relative refractive period
- If there is no stimulus, the VG K+-channels close and membrane potential returns to resting value

Question 12

II. Development of action potential
- AP development in neurons (7 steps)
4B. In step 5, At the top of the spike (+35mV to +40mV), repolarization occurs (restoring the negative charge inside the neuron) due to 2 mechanisms
=> What are these 2 mechanisms?

Answer 12

1/ Slow inactivation gates close on the same VG Na+-channels with a delay
2/ Opening of the VG K+-channels allow inward movement of K+

Question 13

II. Development of action potential
- AP development in neurons (7 steps)
4C. In step 6, The VG K+ channels remain opened
=> What are the consequences?

Answer 13

Causes excessive flow of K+-ions out of the neuron = causes only negative potential inside (hyperpolarization / afterhyperpolarization / undershoot) to -87mV

Question 14

II. Development of action potential
5. What is the definition of Absolute refractory period?

Answer 14

Due to closure of the inactivation gates of the voltage-gated Na+-channels, no new AP can form no matter how strong the stimulus

Question 15

II. Development of action potential
6. What is the definition of Relative refractory period?

Answer 15

Due to hyperpolarization via high K+-permeability through the slow K+-channels responsible for repolarization, any new AP formation would require a stronger than normal stimulus to reach the threshold

Question 16

III. Ionic basis of AP
1. What is the ion basis of AP?

Answer 16

I = current, g = conductance
Eion calculated by Nernst equation

I ion = g ion * (Em - Eion)

Question 17

III. Ionic basis of AP
2A. This is the ion basis of AP
-> Interpret it.

Answer 17

• The early phase of an AP is a result of a rapid increase in gNa, which causes the membrane potential to change toward the Eeq for Na+
• Even though there is the rapid change in gNa, the gK/gNa ratio DOES NOT REACH 0
  -> Membrane potential is driven back toward Eeq for K+ and repolarizes towards its resting value
• Afterhyperpolarization occurs, because gK remains high for a period of time after the AP
  -> As gK returns to its baseline level, the potential returns to its baseline level

Question 18

III. Ionic basis of AP
2B. the gK/gNa ratio DOES NOT REACH 0
=> Why?

Answer 18

1) Rise in gNa with depolarization is transient (short-term)
2) Depolarization leads to a rise in gK -> causes the ratio to stop falling and start increasing

=> Membrane potential is driven back toward Eeq for K+ and repolarizes towards its resting value

Question 19

III. Ionic basis of AP
3. What is the sequence of AP development based on ion basis?

Answer 19

Question 20

IV. Similarities and differences in AP between distinct cells - Cardiac APs
1A. What are the Characteristics of cardiac AP?

Answer 20

• Longer duration: cardiac APs are longer than neuronal APs and range from 150ms in atria to 300ms in Purkinje cells
• Plateau phase: cardiac APs display a depolarized ‘’plateau’’ phase due to slow Ca2+- channels
• Longer refractory periods: due their longer duration (results from plateau phase)

Question 21

IV. Similarities and differences in AP between distinct cells - Cardiac APs
1B. What are the Phases of cardiac AP?

Answer 21

• Phase 0 (upstroke)
• Phase 1 (initial repolarization)
• Phase 2 (plateau)
• Phase 3 (repolarization)
• Phase 4 (electrical diastole)

Question 22

IV. Similarities and differences in AP between distinct cells - Cardiac APs
1C. What happen in Phase 0 (upstroke) of cardiac myocytes APs?

Answer 22

• Rapid depolarization due to increase in Na+-permeability.
• Fast depolarization-induced activation gates on the Na+-channels open, followed by closure of slow depolarization-induced inactivation gates – resulting in a peak voltage of +20mV

Question 23

IV. Similarities and differences in AP between distinct cells - Cardiac APs
1D. What happen in Phase 1 (initial repolarization) of cardiac myocytes APs?

Answer 23

• As Na+-channel inactivation gates close, slow depolarization-activated K+-channels open.
• Both electrical + concentration gradients favor K+-efflux, and thus the membrane repolarizes slightly

Question 24

IV. Similarities and differences in AP between distinct cells - Cardiac APs
1E. What happen in Phase 2 (plateau) of cardiac myocytes APs?

Answer 24

• During the upstroke phase, slow L-type VG Ca2+-channels (the dihydropyridine channel, or DHP channel) begin to activate. Ca2+ flows into the cell – counteracting the initial repolarization effect of K+-efflux leading to the voltage plateau.
• Since the electrical + concentration gradients still strongly favor K+-efflux, K+-permeability cannot be too high or else the cell would repolarize without achieving a plateau.
• Inward-rectifying channels decrease K+-permeability by closing at depolarized voltage, thus allowing this balance of flows
  => This Ca2+-influx also induces Ca2+-release from RyR channels on SR, to maintain excitation-contraction coupling, strengthening muscle contraction

**Note: The ryanodine receptors (RyRs) are a family of Ca2+ release channels found on intracellular Ca2+ storage/release organelles.

Question 25

IV. Similarities and differences in AP between distinct cells - Cardiac APs 1F. What happen in Phase 3 (repolarization) of cardiac myocytes APs?

Answer 25

As Ca2+-permeability decreases and K+-permeability increases, K+-efflux overcomes Ca2+-influx and the cell repolarizes

Question 26

IV. Similarities and differences in AP between distinct cells - Cardiac APs 1G. What happen in Phase 4 (electrical diastole) of cardiac myocytes APs?

Answer 26

membrane potential approaches K+-equilibrium potential, K+-efflux slows down and the cell comes to rest at its Em of -85mV

Question 27

IV. Similarities and differences in AP between distinct cells - SA node APs 2A. What are the Characteristics of SA node AP?

Answer 27

- Upstroke + repolarization phases , but ionic mechanism differs - No stable membrane potential + no plateau - Has automaticity – which leads to the SA node’s spontaneous pacemaker activity - Less negative Em, partially because they do not have inwardly rectifying K+-channels

Question 28

IV. Similarities and differences in AP between distinct cells - SA node APs 2B. What are the Phases of SA node AP?

Answer 28

- Phase 0 (upstroke) - Phase 3 (repolarization) - Phase 4 (pacemaker potential)

Question 29

IV. Similarities and differences in AP between distinct cells - SA node APs 2C. What happen in the Phase 0 (upstroke) of SA node AP?

Answer 29

- Less rapid than in cardiac myocytes. Depolarization occurs slowly with Na+- influx via the ‘’funny channels’’ (If). - At the threshold voltage: T-type VDCCs and L-type VDCCs activate, and Ca2+-influx fully depolarizes the nodal cells

Question 30

IV. Similarities and differences in AP between distinct cells - SA node APs 2D. What happen in the Phase 3 (repolarization) of SA node AP?

Answer 30

As in cardiac myocytes, increased K+-permeability (due to mostly the delayed rectifier K+-current (IK)) repolarizes the cell to about -65mV

Question 31

IV. Similarities and differences in AP between distinct cells - SA node APs 2E. What happen in the Phase 4 (pacemaker potential) of SA node AP?

Answer 31

- As repolarization continues, the cell potential reaches about -50mV, which triggers slow opening of inward Na+-channels – and the funny current begins to slowly depolarize the cell until the threshold potential for the upstroke is met again. - This is why SA node has automaticity and sets the HR. - If the rate of phase 4 increases, the SA node will fire more APs per unit time

Question 32

IV. Similarities and differences in AP between distinct cells - Skeletal muscle APs 3A. What are the characteristics of Skeletal muscle APs?

Answer 32

1/ Similar shape to neuronal APs, but slightly slower repolarization 2/ 5ms total duration

Question 33

IV. Similarities and differences in AP between distinct cells - Skeletal muscle APs 3B. What are the phases of Skeletal muscle APs? What happen in these phases?

Answer 33

1/ Depolarization: opening of VG Na+-channels 2/ Repolarization: closure of Na+-channels + opening of VG K+-channels 3/ Hyperpolarization: VG K+-channels

Question 34

IV. Similarities and differences in AP between distinct cells - Smooth muscle APs 4A. What are the characteristics of Smooth muscle APs?

Answer 34

1/ Compared to neuronal APs – smaller amplitude, longer duration and different ion currents (highly Ca2+-dependent!) 2/ Resting Em is not constant, but oscillates between -40 to -80mV, in so called slow waves, which are initiated by pacemaker interstitial cells of Cajal between the wall’s two muscular layers of f.ex. GI-tract 3/ Slow waves are conducted to the GI SM layers via gap junctions on processes of Cajal cells. Frequency from 3/min in stomach -> 12/min in duodenum - Induce only weak contraction, but if voltage of the slow wave meets a threshold, APs may be triggered on top of the wave increasing the force of contraction. - More AP peaks = stronger SM contractions

Question 35

IV. Similarities and differences in AP between distinct cells - Smooth muscle APs 4B. What are the ion mechanisms of Smooth muscle APs?

Answer 35

1/ Depolarization: L-type VDCCs 2/ Repolarization: late voltage-gated K+- channel 3/ Plateau phase: Ca2+-activated K+-channel

Question 36

V. Conduction of action potentials 1. What are the 3 steps of AP conduction?

Answer 36

1. Initial segment is depolarized such that the cytosol Is positive; adjacent area remains at resting membrane potential 2. Positive charges inside the initial segment flows down the axon to adjacent areas, and the positive charge outside flows oppositely 3. Adjacent area depolarize to threshold, opening of ion channels and firing an AP. Initial segment repolarizes back to resting membrane potential

Question 37

V. Conduction of action potentials 2A. What are the 2 factors of AP conduction velocity?

Answer 37

1) Axon diameter 2) Myelination

Question 38

V. Conduction of action potentials 2B. How can axon diameter affect AP conduction velocity?

Answer 38

Larger axon diameter = higher conduction velocity because resistance is inversely proportional to cross-sectional area (R = V/CSA)

Question 39

V. Conduction of action potentials 2C1. What does myelin consist of?

Answer 39

Myelin consists of plasma membrane of certain cells that insulate the nerve fiber - Schwann cells (PNS ) and oligodendrocytes (CNS)

Question 40

V. Conduction of action potentials 2C2. How can myelination affect AP conduction velocity?

Answer 40

1/ Myelin increases the membrane resistance + decreases membrane capacitance -> Less current is lost through the membrane per length of axon 2/ Unmyelinated nodes of Ranvier at 1-2mm intervals allow the necessary current to flow in/out for AP propagation - the current ‘’jumps’’ at higher speeds between the nodes = saltatory conduction greatly increases the velocity => AP jumps from one node of Ranvier (unmyelinated part of axon) to the next

Question 41

V. Conduction of action potentials 3. What is the relationship between space constant and AP conduction velocity?

Answer 41

- Space constant↑ = speed of propagation↑ - RIC↓ = diameter of axon↑ - Rmembrane ↑ - myelin

Question 42

VI. How is AP controlled?

Answer 42

- Inhibitors of voltage-dependent Na+-channels (lidocaine) - [Ca2+]plasma ↑ = Ethr more positive - [Ca2+]plasma ↓ = Ethr more negative - [K+] – repolarization