Electrophysiology - Goldspink

Question 1

What ion essentially sets the resting membrane potential of caridomyocytes?

Why?

Knowing this, how can you mathematically approximate the resting membrane potential?

What phase of the action potential is resting potential referred to as?

Answer 1

K⁺

Because only K⁺ channels are open at rest.

Calculate the Nenst (Equilibrium) potential of K⁺

Phase 4

Question 2

Flux of which ion is responsible for the rapid upstroke (phase 0) of the AP in non-pacemaker cells?

Answer 2

Na⁺

Question 3

Flux of which ion is primarily responsible for depolarization in pacemaker cells?

What phase of the AP does this flux occur during?

Answer 3

Ca²⁺

Phase 2

Question 4

Flux of which ion is responsible for repolarization?

What phase of the AP does this correspond to?

Answer 4

K⁺

Phase 3

Question 5

What transporters work to reduce intracellular Ca²⁺ after depolarization occurs?

Where is the Ca2⁺ sequestered to?

Answer 5

Na⁺/Ca²⁺ exchanger & active Ca²⁺ transporters

CaExtracellular fluid and sarcoplasmic reticulum.

Question 6

What channel maintains the Na⁺and K⁺ concentration gradients in cardiomyocytes?

Answer 6

Na⁺/K⁺ ATPase

Question 7

What channel is especially important in the generation of cardiac rhythmicity?

What do they transport? What direction?

When are they activated? Inactivated?

Answer 7

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. They help generate the “funny” or pacemaker current.

Cation nonspecific (Na⁺/K⁺) - Inward

Whats “funny” about HCN channels is that while they are depolarizing, they do not activate to aid initial AP depolarization, but rather work to offset hyperpolarization that occurs after repolarization in phase 3 of the AP. To this end, they activate slowly and do not inactivate.

Question 8

Ion channel structure:

1) How many domains does an ion channel feature?
2) How many transmembrane segments make up a domain?
3) Which segment in a domain is important in sensing voltage?
4) Where is the selectivity filter portion of each domain?
5) Where is the inactivation gate located?

Answer 8

1) Four
2) Six
3) The fourth segment (S₄) in each domain
4) The loop between S₅and S₆ in each domain
5) The loop between Domains III and IV (only one per channel)

Question 9

Ion Channel Structure:

1) On what side of the ion channel is the selectivity filter closest to?
2) On what side of the channel is the inactivation gate closest to?

Answer 9

1) Selectivity filter: Extracellular side
2) Inactivation gate: Cytosolic side

Question 10

Once an Na⁺ channel inactivation gate has closed, when will it open again?

Answer 10

When resting membrane potential is reached.

Question 11

At resting membrane potential, what is the direction of:

1) The chemical gradient of K⁺
2) The electrical gradient of K⁺

(Bonus: What is value of the resting membrane potential?)

Answer 11

1) Outward (out of cell)
2) Inward (in to cell)

Bonus: -91mV

Question 12

During an AP, why does the membrane voltage plateau for a short time before most of repolarization occurs?

Answer 12

The repolarizing effect of K⁺efflux is offset by Ca²⁺ influx during this phase.

Question 13

What inactivates K⁺ion channels?

Answer 13

The high membrane voltages reached due to depolarization during an AP.

Question 14

What channel does not contribute to the AP in pacemaker cells?

Why does this happen?

Answer 14

Fast Na⁺ current channels

Pacemaker cells chronically exist in a state of less-negative potential than typical resting memrane potential. At this potential, fast Na⁺ channels will always be inactivated and thus do not contribute to the AP in pacemaker cells.

Question 15

What are the three subtypes of repolarizing K⁺current?

Answer 15

1) I_{Kur - Ultrarapid}
2) IKr - Rapid
3) IKs - Slow

Question 16

How does acetylcholine slow heart rate?

What is the name of the ion channel involved in this process?

Answer 16

Ach binds Muscarinic receptors in cardiac pacemaker cells, causing hyperpolarization by inward K⁺ flux. This slows the pacemaker rate as well as condunction through the AV node, slowing heart rate.

Ion Channel: **GIRK **(G protein-coupled inwardly-rectifying K⁺ channels)

Question 17

What is odd about the inward rectifying K⁺ current?

Answer 17

It is primarily an inward K⁺ current (repolarizing effect), but can display some transient outward K⁺ flux at the beginning of phase 4 (when resting potential is first re-established after an AP.)

Why? No idea. Important? Who knows, but Goldspink made a point of talking about it.

Question 18

What can explain the slower condunction through the AV node than through the SA node?

Answer 18

AV nodal cells share fewer gap junctions than SA nodal cells, so AP condunction from cell to cell is slower in the AV node.

Question 19

What current initially drives depolarization in pacemaker cells?

In non-pacemaker cardiomyocytes?

Answer 19

Ca²⁺ influx

Na⁺ influx

Question 20

Which heart tissues have generally fast depolarization and conduction?

Which have generally slower depolarization and condunction?

What explains the difference?

Answer 20

Fast: Atria, Ventricles, Purkinje fibers

Slow: SA and AV nodal cells

Why: Lack of fast Na⁺ channels and presence of spontaneously opening slow Ca²⁺ channels in pacemaker cells are believed to cause the difference (as well as the automaticity of pacemaker cells).

Question 21

What stimulates an HCN channel to open?

Answer 21

Voltage (hyperpolarization) or Nucleotide binding

(In the name: Hyperpolarization-activated Cyclic Nucleotide-gated channel)

Question 22

Name an inhibitor for each of the following ion channels:

1) Na⁺
2) K⁺
3) Ca²⁺

Answer 22

1) Na⁺: TTX, local anesthetics
2) K⁺: TEA
3) Ca^2+​: verapamil, nifedipine, etc.

Question 23

What is effect of GIRK channels opening in the SA node?

In the AV node?

Answer 23

SA: Reduces steepness of phase 4 and making the diastolic potential more negative. This slows the pacemaker rate.

AV: The same, but because the AV nodal cells are not the pacemakers, the overall effect is to slow condunction velocity.

Question 24

What is the effect or norepinephrine on SA and AV nodal cells?

What about on atrial and ventricular cells?

Answer 24

SA & AV: Acts on beta-adrenergic receptors to increase steepness of phase 4, increase Ca²⁺ current, and makes the threshold potential more negative.

Atrial & Ventricular: Inotropic effect. Increases Ca²⁺ influx, sensitivity of ryanodine receptor, and CICR from Sarcoplasmic Reticulum. Increases Ca²⁺ binding to troponin, and enhances SERCA pump to increase Ca²⁺ in the SR.

[tl;dr: NE → CALCIUM → Harder Better Faster Stronger]

Question 25

What are 3 mechanisms of altering heart rate at the level of the action potential?

Answer 25

1) Change the rate of depolarization 2) Change the maximum diastolic potential (aka the resting membrane potential) 3) Change the threshold potential

Question 26

What is the absolute refractory period (RP)? What is the effective RP? What is the relative RP? What is the supranormal period?

Answer 26

Absolute: Cell is unexcitable to stimulation Effective: Stimulation produces a localized depolarization that does not propagate Relative: Stimulation produces a weak, slowly propagating AP Supranormal: A weaker-than-normal stimulation with produce an AP

Question 27

How does resting potential affect speed of depolarization during phase 0 of an AP?

Answer 27

Oddly, a **less-negative-than-normal** resting potential results in a **slower** rise of phase 0 and **lower** maximum aplitude of the AP.

Question 28

How does temperature affect heart rate? What is the ratio of change in heart rate to change in temperature?

Answer 28

Heating: Increases SA node firing by increasing slope of phase 4. Cooling: Opposite effect Rate: **10bpm per 1°C difference**

Question 29

What effects does **hyper**kalemia have on heart APs? What findings are found on EKG? What serious complications does hyperkalemia have?

Answer 29

AP effects: Increased resting potential causes **slowed depolarization rate, smaller AP amplitude, and shorterns AP duration by accelerating repolarization**. EKG: Decreased P wave amplitude, widened P-R interval and QRS complex, shortened Q-T interval and **characteristic tall T-wave peaks**. Complications: AV nodal block, ventricular fibrillation, sudden death (see dissapearance of P wave).

Question 30

What effects does **hypo**kalemia have on heart APs? What findings are found on EKG? What serious complications does hyperkalemia have?

Answer 30

AP: Decrease in resting potential, slowing of repolarization, prolongation of AP duration EKG: Flattened T wave, prolongation of P-R and QT intervals Complications: AV block, ventricullar fibrillation.

Question 31

What effects does **hyper**calcemia have on heart APs? What findings are found on EKG?

Answer 31

AP: Shortening of phase 2 and thus shorter AP duration EKG: Shortened ST segment and thus Q-T interval

Question 32

What effects does **hypo**calcemia have on heart APs? What findings are found on EKG?

Answer 32

AP: Prolonging of phase 2 and thus longer AP duration EKG: Prolonged ST segment and thus Q-T interval

Question 33

During and AP, downstream spread of positive intracellular current produces and equal and opposite discharge of positive ions and the flow of positive extracellular charge upstream. What can the extracellular currents be measured to determine?

Answer 33

The vectors that make up the EKG.

Question 34

Name 3 indications for beta-blocker or calcium channel blockers.

Answer 34

1) Hypertension 2) Angina 3) Arrhythmias (slows rate of pacemaker depolarization) beta blockers also can be used for MIs