Cardiac action potential

Unlike the action potential in skeletal muscle cells, the cardiac action potential is not initiated by nervous activity. Instead, it arises from a group of specialized cells known as pacemaker cells, that have automatic action potential generation capability. In healthy hearts, these cells form the cardiac pacemaker and are found in the sinoatrial node in the right atrium. They produce roughly 60–100 action potentials every minute. The action potential passes along the cell membrane causing the cell to contract, therefore the activity of the sinoatrial node results in a resting heart rate of roughly 60–100 beats per minute. All cardiac muscle cells are electrically linked to one another, by intercalated discs which allow the action potential to pass from one cell to the next. This means that all atrial cells can contract together, and then all ventricular cells. SA node is the main pacemaker of the heart having maximum P cells.
Rate dependence of the action potential is a fundamental property of cardiac cells and alterations can lead to severe cardiac diseases including cardiac arrhythmia and sometimes sudden death.
Action potential activity within the heart can be recorded to produce an electrocardiogram. This is a series of upward and downward spikes that represent the depolarization and repolarization of the action potential in the atria and ventricles.

Overview

Similar to skeletal muscle, the resting membrane potential of ventricular cells is around −90 millivolts, i.e. the inside of the membrane is more negative than the outside. The main ions found outside the cell at rest are sodium, and chloride, whereas inside the cell it is mainly potassium.
The action potential begins with the voltage becoming more positive; this is known as depolarization and is mainly due to the opening of sodium channels that allow Na⁺ to flow into the cell. After a delay, the action potential terminates as potassium channels open, allowing K⁺ to leave the cell and causing the membrane potential to return to negative, this is known as repolarization. Another important ion is calcium, which can be found inside the cell in the sarcoplasmic reticulum where calcium is stored, and is also found outside of the cell. Release of Ca²⁺ from the SR, via a process called calcium-induced calcium release, is vital for the plateau phase of the action potential and is a fundamental step in cardiac excitation-contraction coupling.
There are important physiological differences between the pacemaker cells of the sinoatrial node, that spontaneously generate the cardiac action potential and those non-pacemaker cells that simply conduct it, such as 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 shown in figure 2.

Cardiac automaticity

Cardiac automaticity also known as autorhythmicity, is the property of the specialized conductive muscle cells of the heart to generate spontaneous cardiac action potentials. Automaticity can be normal or abnormal, caused by temporary ion channel characteristic changes such as certain medication usage, or in the case of abnormal automaticity the changes are in electrotonic environment, caused, for example, by myocardial infarction.

Phases

The standard model used to understand the cardiac action potential is that of the ventricular myocyte. Outlined below are the five phases of the ventricular myocyte action potential, with reference also to the SAN action potential.

Phase 4

In the ventricular myocyte, phase 4 occurs when the cell is at rest, in a period known as diastole. In the standard non-pacemaker cell the voltage during this phase is more or less constant, at roughly -90 mV. The resting membrane potential results from the flux of ions having flowed into the cell, the flux of ions having flowed out of the cell, as well as the flux of ions generated by the different membrane pumps, being perfectly balanced.
The activity of these pumps serve two purposes. The first is to maintain the existence of the resting membrane potential by countering the depolarisation due to the leakage of ions not at the electrochemical equilibrium. These ions not being at the equilibrium is the reason for the existence of an electrical gradient, for they represent a net displacement of charges across the membrane, which are unable to immediately re-enter the cell to restore the electrical equilibrium. Therefore, their slow re-entrance in the cell needs to be counterbalanced or the cell would slowly lose its membrane potential.
The second purpose, intricately linked to the first, is to keep the intracellular concentration more or less constant, and in this case to re-establish the original chemical gradients, that is to force the sodium and calcium which previously flowed into the cell out of it, and the potassium which previously flowed out of the cell back into it.
For example, the sodium and potassium ions are maintained by the sodium-potassium pump which uses energy to move three Na⁺ out of the cell and two K⁺ into the cell. Another example is the sodium-calcium exchanger which removes one Ca²⁺ from the cell for three Na⁺ into the cell.
During this phase the membrane is most permeable to K⁺, which can travel into or out of cell through leak channels, including the inwardly rectifying potassium channel. Therefore, the resting membrane potential is mostly equal to K⁺ equilibrium potential and can be calculated using the Goldman-Hodgkin-Katz voltage equation.
However, pacemaker cells are never at rest. In these cells, phase 4 is also known as the pacemaker potential. During this phase, the membrane potential slowly becomes more positive, until it reaches a set value or until it is depolarized by another action potential, coming from a neighboring cell.
The pacemaker potential is thought to be due to a group of channels, referred to as HCN channels. These channels open at very negative voltages and allow the passage of both K⁺ and Na⁺ into the cell. Due to their unusual property of being activated by very negative membrane potentials, the movement of ions through the HCN channels is referred to as the funny current.
Another hypothesis regarding the pacemaker potential is the 'calcium clock'. Calcium is released from the sarcoplasmic reticulum within the cell. This calcium then increases activation of the sodium-calcium exchanger resulting in the increase in membrane potential but only a +2 charge is leaving the cell. This calcium is then pumped back into the cell and back into the SR via calcium pumps.

Phase 0

This phase consists of a rapid, positive change in voltage across the cell membrane lasting less than 2 ms in ventricular cells and 10–20 ms in SAN cells. This occurs due to a net flow of positive charge into the cell.
In non-pacemaker cells, this is produced predominantly by the activation of Na⁺ channels, which increases the membrane conductance of Na⁺. These channels are activated when an action potential arrives from a neighbouring cell, through gap junctions. When this happens, the voltage within the cell increases slightly. If this increased voltage reaches the threshold potential it causes the Na⁺ channels to open. This produces a larger influx of sodium into the cell, rapidly increasing the voltage further to around +50 mV, i.e. towards the Na⁺ equilibrium potential. However, if the initial stimulus is not strong enough, and the threshold potential is not reached, the rapid sodium channels will not be activated and an action potential will not be produced; this is known as the all-or-none law. The influx of calcium ions through L-type calcium channels also constitutes a minor part of the depolarisation effect. The slope of phase 0 on the action potential waveform represents the maximum rate of voltage change of the cardiac action potential and is known as dV/dt_max.
In pacemaker cells, however, the increase in membrane voltage is mainly due to activation of L-type calcium channels. These channels are also activated by an increase in voltage, however this time it is either due to the pacemaker potential or an oncoming action potential. The L-type calcium channels are activated more slowly than the sodium channels, therefore, the depolarization slope in the pacemaker action potential waveform is less steep than that in the non-pacemaker action potential waveform.

Phase 1

This phase begins with the rapid inactivation of the Na⁺ channels by the inner gate, reducing the movement of sodium into the cell. At the same time potassium channels open and close rapidly, allowing for a brief flow of potassium ions out of the cell, making the membrane potential slightly more negative. This is referred to as a 'notch' on the action potential waveform.
There is no obvious phase 1 present in pacemaker cells.

Phase 2

This phase is also known as the "plateau" phase due to the membrane potential remaining almost constant, as the membrane slowly begins to repolarize. This is due to the near balance of charge moving into and out of the cell. During this phase delayed rectifier potassium channels allow potassium to leave the cell while L-type calcium channels allow the movement of calcium ions into the cell. These calcium ions bind to and open more calcium channels located on the sarcoplasmic reticulum within the cell, allowing the flow of calcium out of the SR. These calcium ions are responsible for the contraction of the heart.
Calcium also activates chloride channels called I_to2, which allow Cl⁻ to enter the cell. Increased calcium concentration in the cell also increases activity of the sodium-calcium exchangers, while increased sodium concentration increases activity of the sodium-potassium pumps. The movement of all these ions results in the membrane potential remaining relatively constant, with K⁺ outflux, Cl⁻ influx as well as Na⁺/K⁺ pumps contributing to repolarisation and Ca²⁺ influx as well as Na⁺/Ca²⁺ exchangers contributing to depolarisation. This phase is responsible for the large duration of the action potential and is important in preventing irregular heartbeat.
There is no plateau phase present in pacemaker action potentials.