Question

Compare and contrast the molecular events of the action potential in the pacemaker cells of the SA node to those in a ventricular (contractile) cardiomyocyte. Be sure to point out how these molecular events underlie the differences in the shapes of the two types of potentials and how these differences serve the difference in functions for these cell types.

Answer 1

The cardiac action potential is a brief change in voltage (membrane potential) across the cell membrane of heart cells.^[1] This is caused by the movement of charged atoms (called ions) between the inside and outside of the cell, through proteins called ion channels.

The changes in membrane potential during the different phases are brought about by changes in the movement of ions (principally Ca⁺⁺ and K⁺, and to a lesser extent Na⁺) across the membrane through ion channels that open and close at different times during the action potential. When a channel is opened, there is increased electrical conductance (g) of specific ions through that ion channel. Closure of ion channels causes ion conductance to decrease. As ions flow through open channels, they generate electrical currents (i or I) that change the membrane potential.

There are important physiological differences between the cells that spontaneously generate the action potential (pacemaker cells; e.g. SAN) and those that simply conduct it (non-pacemaker cells; e.g. ventricular myocytes). The specific differences in the types of ion channels expressed and mechanisms by which they are activated results in differences in the configuration of the action potential waveform,

As with myocyte contraction, this process is synchronized with the electrical activity of the cell.

• L-type Ca²⁺ channels inactivate toward the end of phase 2 → Ca²⁺ influx arrests → CICR trigger is abolished.
• At the same time, Ca²⁺ is sequestered back into the SR by sarcoplasmic reticulum Ca²⁺ ATPase (SERCA) and pumped out of the cell to a lesser extent by specialized Ca²⁺ pumps.
• Ca²⁺ ions dissociate from TnC as their intracellular concentration falls, and tropomyosin inhibition of actin-myosin interaction is restored.

In the SA node, three ions are particularly important in generating the pacemaker action potential. The role of these ions in the different action potential phases are illustrated below

At the end of repolarization, when the membrane potential is very negative (about -60 mV), ion channels open that conduct slow, inward (depolarizing) Na⁺ currents. These currents are called "funny" currents and abbreviated as "I_f". These depolarizing currents cause the membrane potential to begin to spontaneously depolarize, thereby initiating Phase 4. As the membrane potential reaches about -50 mV, another type of channel opens. This channel is called transient or T-type Ca⁺⁺ channel. As Ca⁺⁺ enters the cell through these channels down its electrochemical gradient, the inward directed Ca⁺⁺ currents further depolarize the cell. When the membrane depolarizes to about -40 mV, a second type of Ca⁺⁺ channel opens. These are the so-called long-lasting, or L-type Ca⁺⁺ channels. Opening of these channels causes more Ca⁺⁺ to enter the cell and to further depolarize the cell until an action potential threshold is reached (usually between -40 and -30 mV). It should be noted that a hyperpolarized state is necessary for pacemaker channels to become activated. Without the membrane voltage becoming very negative at the end of phase 3, pacemaker channels remain inactivated, which suppresses pacemaker currents and decreases the slope of phase 4. This is one reason why cellular hypoxia, which depolarizes the cell and alters phase 3 hyperpolarization, leads to a reduction in pacemaker rate (i.e., produces bradycardia). During Phase 4 there is also a slow decline in the outward movement of K⁺ as the K⁺ channels responsible for Phase 3 continue to close. This fall in K⁺ conductance (gK⁺) contributes to the depolarizing pacemaker potential.

Phase 0 depolarization is primarily caused by increased Ca⁺⁺ conductance (gCa⁺⁺) through the L-type Ca⁺⁺ channels that began to open toward the end of Phase 4. The "funny" currents, and Ca⁺⁺ currents through the T-type Ca⁺⁺ channels, decline during this phase as their respective channels close. Because the movement of Ca⁺⁺ through these channels into the cell is not rapid, the rate of depolarization (slope of Phase 0) is much slower than found in other cardiac cells (e.g., Purkinje cells).

Repolarization occurs (Phase 3) as K⁺ channels open (increased gK⁺) thereby increasing the outward directed, hyperpolarizing K⁺ currents. At the same time, the L-type Ca⁺⁺ channels become inactivated and close, which decreases gCa⁺⁺ and the inward depolarizing Ca⁺⁺ currents.