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Cardiac action potential

As in other cells, the cardiac action potential is a short-lasting event in which the difference of potential between the interior and the exterior of each cardiac cell rises and falls following a consistent trajectory.[1]

The cardiac action potential differs significantly in different portions of the heart. The heart is provided with a special excitatory system and a contractile system necessary to differentiate action potentials in the heart, which allow this organ to function at a constant rate.

This differentiation of the action potentials allows the different electrical characteristics of the different portions of the heart. For instance, the specialized excitatory system of the heart has the special property of spontaneous depolarization.This means the heart depolarizes without any external influence via a slow, positive increase in voltage across the cell's membrane (the membrane potential) that occurs between the end of one action potential and the beginning of the next action potential. This increase in membrane potential (depolarization) typically permits the membrane potential to reach the threshold potential at which it fires the next action potential (pacemaker potential). Thus, the pacemaker potential is what drives the self-generated rhythmic firing. This is known as cardiac muscle automaticity or autorhythmicity.[2]

Pacemaker potentials are fired by sinoatrial node (SAN), but also by the other foci. However, the last ones have firing frequencies slower than the SAN's. When other foci attempt to fire at their intrinsic rate, they can't because they have been discharged by the previous electric impulse coming from the SAN before their pacemaker potential threshold is reached. This is called "overdrive suppression".[3] It should be noted that under certain conditions (if pacemaker cells become compromised) non-pacemaker cells can take over and set the pace of the heart (become pacemakers). Rate dependence of action potential is a fundamental property of cardiac cells. This is important for the QT interval, measured from the beginning of the QRS complex to the end of the T wave. This interval must be corrected for the cardiac rhythm QTc. A prolonged QTc, long QT syndrome, induced by drugs or disease congenital or acquired, increases the possibility of developing severe ventricular arrhythmias and sometimes sudden death.[4]

The electrical activity of the specialized excitatory tissues is not apparent on the surface electrocardiogram (ECG). This is due to the relatively small time duration. It is not possible, for example, to see on the ECG the sinus node activity but the resulting atrial myocardium contraction is apparent as a wave: the P wave. The electrical activity of the conducting system can be seen on the ECG (for example the AV node delay and the so-called PR segment).[5]


Intra- and extracellular ion concentrations (mmol/L)
Element Ion Extracellular Intracellular Ratio
Sodium Na+ 135 - 145 10 14:1
Potassium K+ 3.5 - 5.0 155 1:30
Chloride Cl 95 - 110 10 - 20 4:1
Calcium Ca2+ 2 10−4 2 x 104:1
Although intracellular Ca2+ content is about 2 mM, most of this is bound or sequestered in intracellular organelles (mitochondria and sarcoplasmic reticulum).[6]

Cardiac action potentials are generated by the movement of ions through the transmembrane ion channels in the cardiac cells.[7]

Cardiac muscle bears some similarities to skeletal muscle, as well as important differences. Like skeletal myocytes (and axons for that matter), in the resting state a given cardiac myocyte has a negative membrane potential. Within the cell K+(potassium) is the principal cation, and phosphate and the conjugate bases of organic acids are the dominant anions. Outside the cell Na+ (sodium) is the principal cation and Cl (chloride) is the dominant anion. A notable difference between skeletal and cardiac myocytes is how each elevates the myoplasmic Ca2+ to induce contraction. When skeletal muscle is stimulated by somatic motor axons, influx of Na+ quickly depolarizes the skeletal myocyte and triggers calcium release from the sarcoplasmic reticulum. However, in cardiac myocytes the release of Ca2+ from the sarcoplasmic reticulum is induced by Ca2+ influx into the cell through voltage-gated calcium channels on the sarcolemma. This phenomenon is called calcium-induced calcium release and increases the myoplasmic free Ca2+ concentration causing muscle contraction. In both muscle types, after a delay (the absolute refractory period), potassium channels reopen and the resulting flow of K+ out of the cell causes repolarization. The voltage-gated calcium channels in the cardiac sarcolemma are generally triggered by an influx in sodium during the "0" phase of the action potential (see below). Cardiac muscle is a syncytium in which the cardiac muscle cells are so tightly bound that when one of these cells is excited the action potential spreads to all of them and allows succinct coordinated contraction of the heart. Cardiac pacemaker cells (autorhythmic cells) are connected to adjoining contractile cells (non-pacemaker cells) via gap junctions. Gap junctions allow the spontaneous depolarization and action potential generated by pacemaker cells to be transferred to contractile cells.[8][9] Of all the cells in the body, only heart cells are able to contract on their own without stimulation from the nervous system.

Note that there are important physiological differences between excitatory cells and muscular cells; the specific differences in ion channels and mechanisms of polarization give rise to unique properties of excitatory cells, most importantly the spontaneous depolarization (cardiac muscle automaticity) necessary for the SAN pacemaker activity.[7] Atrial myocytes, ventricular myocytes and Purkinje cells are examples of non-pacemaker action potentials in the heart. Because these action potentials undergo very rapid depolarization, they are sometimes referred to as "fast response" action potentials [10]

Phases of the cardiac action potential

File:Action potential ventr myocyte.gif
Image 1: Standard model of a cardiomyocyte action potential[7]
File:Pacemaker potential annotated.gif
Image 2: The cardiac pacemaker cell action potential


The standard model used to understand the cardiac action potential is the action potential of the ventricular myocyte, which are cardiac contractile muscle fibers in the lower chambers of the heart. The action potential has 5 phases (numbered 0-4).

Phase 4

Phase 4 is the resting membrane potential, and describes the membrane potential when the cell is not being stimulated. So in the standard myocyte model this phase will be a horizontal line. This is what happens in 99% of cardiac cells, which are contractile cells. [7] The resting membrane potential is caused by the difference in ionic concentrations and conductances across the cell membrane during phase 4 of the action potential. The normal resting membrane potential in the ventricular myocardium is about -85 to -95 mV. This potential is determined by the selective permeability of the cell membrane to various ions. The membrane is most permeable to K+ (mainly due to leak channels) and relatively impermeable to other ions. The resting membrane potential is therefore dominated by the K+ equilibrium potential (-80mV) according to the K+ gradient across the cell membrane. The membrane potential can be calculated using the Goldman-Hodgkin-Katz voltage equation. The maintenance of this electrical gradient is due to various ion pumps and exchange mechanisms, which use ATP (energy) to pump ions against their electrochemical gradient. Some of which include the Na+-K+ ion exchange pump, the Na+-Ca2+ exchanger current and the IK1 inwardly rectifying K+ current. I is the symbol for an electric current.[11]

However, phase 4 is also special and very important because all cardiac cells, which belong to the excitatory system have an unstable phase 4 - is the pacemaker potential. All can fire an electric impulse as the SAN does. So, in these cells, the phase 4 is as the image 2 shows: the membrane slowly depolarizes until it reaches a threshold potential (around -40mV) or until it is depolarized by an electrical impulse coming from another cell. The reason for this pacemaker potential is an increased inward current of sodium (Na+) through voltage-dependent channels, but also an increased inward calcium current and a slowly decreasing potassium outward current. These sodium channels, in cardiac pacemaker cells, have a particular behavior because, contrary to what usually happens in other cells, they open when the voltage is more negative, immediately after the end of a previous action potential. For this reason they are called "funny channels".[7]

The little Purkinje fibers [nb 1] usually don't depolarize spontaneously simply because, before reaching the threshold potential, they are depolarized by an impulse coming from the SAN: their pacemaker potential is suppressed by the more rapid rate of the SA node pacemaker. In phase 4 of the SAN, spontaneous depolarization occurs faster than in all the other cardiac cells (60-100 action potentials per minute), so it leads the cardiac rhythm and maintains a hierarchy.[7] However, under some circumstances the little Purkinje fibres can depolarize and originate an atrial or ventricular premature beat. An example of ventricular premature contraction without pathology is the classic athletic heart syndrome: the sustained training induces a cardiac adaptation in a way that the resting SAN rate is slower (sometimes around 40/min) and this gives time to some ventricular cells to spontaneously reach the threshold potential (-40mV) and depolarize. Typically, these individuals have premature beats at rest which disappear at higher SAN frequencies.[12]

Phase 4 is associated with heart diastole (relaxation) so is called diastolic depolarization. These cardiac cells (the SAN cells especially) are self-activating. Though they do receive some input from the autonomic nervous system, which includes both parasympathetic and sympathetic branches, they need no stimulus to fire. It is the duration of this slow diastolic depolarization, which controls the cardiac chronotropism (REFRENCE). It is also important to point out that the modulation by the autonomic system of the cardiac SAN rate also takes place in this phase. Sympathetic stimuli, responsible for fight or flight responses, induce the acceleration of rate by increasing the slope of the pacemaker phase and decreasing time between subsequent pacemaker action potentials, while parasympathetic activation (stable, at rest functions) exerts the opposite action.[13]

Phase 0

Once the cell is electrically stimulated (typically by an electric current from an adjacent cell through gap junctions), it begins a sequence of actions involving the influx and efflux of cations and anions that together produce the action potential of the cell. Phase 0 is the rapid depolarization phase. Action potentials are unidirectional, all-or-none signals, because once they are initiated they only fire/move in one direction and happen fully at constant strength or not at all.[14][15]

The slope of phase 0 represents the maximum rate of potential change and is known as dV/dtmax. Its behavior is different in contractile and pacemaker heart cells.

In heart muscle cells, this slope is directly proportional to the net ionic current.[16] This phase is due to the opening of the fast Na+ channels causing a rapid increase in the membrane conductance to Na+ (gNa)[nb 2] and thus a rapid influx of Na+ ions (INa) into the cell; a Na+ current. The membrane potential is reversed from negative to positive and peaks at about +25mV inside the cell.The ability of the cell to open the fast Na+ channels during phase 0 is related to the membrane potential at the moment of excitation. If the membrane potential is at its baseline (about -90 mV), all the fast Na+ channels will be in the closed conformation, however when the cell is slightly depolarized via influx of cations through gap junctions the slight depolarization will flip the voltage-gated Na+ channels to the open confirmation, thus causing a large influx of Na+ ions down their electrochemical gradient. If, however, the membrane potential is more negative (hyperpolarized), some of the fast Na+ channels will be in an inactivated state making them insensitive to opening, thus causing a lowered response to a stimulus of the same strength. For this reason, if the resting membrane potential becomes too negative, the cell may not be excitable, and conduction through the heart may be delayed, increasing the risk of arrhythmias.[17]

In heart pacemaker cells, phase 0 depends on the activation of L-type calcium channels instead of the fast Na+ current. The action potentials in autorhythmic cells are caused by the large influx of calcium ions not sodium ions like in contractile cells (threshold -40mV). For this reason, this slope is more gradual (image 2).[18]

Phase 1

Phase 1 of the myocyte action potential occurs with the inactivation of the fast Na+ channels. The transient net outward current causing the small downward deflection of the action potential is due to the movement of K+ and Cl ions, carried by the Ito1 and Ito2 currents, respectively. Particularly the Ito1 contributes to the "notch" of some ventricular cardiomyocyte action potentials (image 1).

It has been suggested that Cl ions movement across the cell membrane during Phase I is as a result of the change in membrane potential, from K+ efflux, and is not a contributory factor to the initial repolarization ("notch").

In cardiac pacemaker cells this phase is due to a rapid outflow of K+ and the closure of the L-type Ca2+ channels.[19]

Phase 2

This "plateau" phase of the cardiac action potential (absent in pacemaker cells), is sustained by a balance between inward movement of Ca2+ (ICa) through L-type calcium channels (opened in response to large depolarization), and outward movement of K+ through the slow delayed rectifier K channel, IKs. The influx of calcium into the cell is balanced by in the efflux of potassium out of the cell, which results in the plateau in action potential graph. The sodium-calcium exchanger current, INa,Ca and the sodium/potassium pump current, INa,K also play minor roles during phase 2,as they begin to restore ion concentrations. The large concentration of intracellular calcium initiates contraction of those cells, which is sustained in the plateau phase.[20] During the plateau phase there is reduced potassium ion permeability. The ion particularly responsible for Plateau formation is Ca2+ (influx).

Phase 3

During phase 3 (the "rapid repolarization" phase) of the action potential, the L-type Ca2+ channels close, while the slow delayed rectifier (IKs) K+ channels remain open as more potassium leak channels open. This ensures a net outward positive current, corresponding to negative change in membrane potential, thus allowing more types of K+ channels to open. These are primarily the rapid delayed rectifier K+ channels (IKr) and the inwardly rectifying K+ current, IK1. This net outward, positive current (equal to loss of positive charge from the cell) causes the cell to repolarize. The delayed rectifier K+ channels close when the membrane potential is restored to about -85 to -90 mV, while IK1 remains conducting throughout phase 4, which helps to set the resting membrane potential[21] Ionic pumps as discussed above, like the sodium-calcium exchanger and the sodium/potassium pump restore ion concentrations back to balanced states pre-action potential. This means that the intracellular calcium is pumped out, which was responsible for cardiac myocyte contraction. Once this is lost the contraction stops and myocytic cells relax, which in turn relaxes the heart muscle.

Refractory period

From the beginning of phase 0 until part way through phase 3 when the membrane potential reaches -60mV, each cell is in an absolute refractory period, also known as the effective refractory period, during which it is impossible to evoke another action potential. This is immediately followed until the end of phase 3 by a relative refractory period, during which a stronger-than-usual stimulus is required.[22][23] These two refractory periods are caused by changes in the state of sodium and potassium channel molecules. After rapid depolarization of the cell due to rapid influx of sodium ions the Vm (membrane potential) approaches 0mV and approaches sodium’s equilibrium potential, which relinquishes sodium’s electrochemical drive into the cell. Sodium channels than enter an "inactivated" state, due to closing of the sodium inactivation gate, in which they cannot be opened regardless of the strength of the excitatory stimulus—this gives rise to the absolute refractory period. The relative refractory period is due to the leaking of potassium ions, which hyperpolarizes Vm (membrane potential) back to normal, thus resetting the sodium channels; opening the inactivation gate, but still leaving it in the closed conformation. Even after a sufficient number of sodium channels have transitioned back to their resting state, a lot of potassium leak channels remain open, thus hyperpolarizing the cell to below normal Vm, making it difficult but possible for depolarization to occur and an action potential to be initiated. The stimulus must be stronger than normal to activate an action potential during the relative refractory period.[24]

Gap Junctions

Gap junctions allow the spontaneous depolarization and action potential generated by pacemaker cells to be transferred to contractile cells. Positive ions move through these cell-to-cell cytoplasmic connections (gap junctions) from pacemaker (autorhythmic) cells to contractile cells and between neighboring contractile cells. This flow of positive ions initiate small voltage changes in contractile cells (Vm goes from about -90mV to -85mV) that depolarize the proximal Na+ voltage-gated channels enough that they flip open, and allow sodium to flow into the cell and depolarize it further. It is through these connections that the pacemaker cells are able to set the rate of contraction for all contractile cells of the heart.Uncoordinated contraction of myocytes and the interruption of normal automaticity are the root of many heart disorders such as tachycardia and bradycardia, so the importance of gap junctions cannot be overlooked when discussing cardiac action potentials.[25]


As explained above, an action potential is due to various ions’ motion into and out of the cell, which depolarizes the membrane potential or the voltage across the membrane. This ion current happens through the so-called Ion channels. Each ion has his specific channel or channels. On the other hand, each channel has gates which open and close under multiple triggering events. These channels are proteins composed by several subunits, and under certain “activating” conditions (presence of a ligand or voltage change) these subunits undergo a conformational (shape) change, which opens a gate to an aqueous channel that permits the ion to rapidly travel across the lipid bilayer. Without this aqueous pore through the membrane an ion’s movement through would be impossible because the lipid bilayer is nonpolar, and therefore impermeable to a charged particle, like an ion.[26]

These channels are selective for specific ions so there are Na+, K+, Ca2+, Cl specific channels. There are also channels that allow ions of a certain charge (positive or negative) to move across the membrane, such as monovalent and multivalent cation channels. Each ion has different channels, which are used in different situations. Most of them are controlled by the membrane potential or localized voltage that is near to them and are the so-called voltage-gated ion channels. Others, are ligand-gated channels which means they open in response to the binding of a chemical ligand (small signaling molecule) to the extracellular or intracellular domain of that particular channel.[26]

Major currents during the cardiac ventricular action potential[8]
Ion Current (I) α subunit protein α subunit gene Phase / role
Na+ INa NaV1.5 SCN5A[27] 0
Ca2+ ICa(L) CaV1.2 CACNA1C[28] 0-2
K+ Ito1 KV4.2/4.3 KCND2/KCND3 1, notch
K+ IKs KV7.1 KCNQ1 2,3
K+ IKr KV11.1 (hERG) KCNH2 3
K+ IK1 Kir2.1/2.2/2.3 KCNJ2/KCNJ12/KCNJ4 3,4
Na+, Ca2+ INaCa 3Na+-1Ca2+-exchanger NCX1 (SLC8A1) ion homeostasis
Na+, K+ INaK 3Na+-2K+-ATPase ATP1A ion homeostasis
Ca2+ IpCa Ca2+-transporting ATPase ATP1B ion homeostasis

Voltage-gated ion channels have transmembrane voltage sensors. Ligand-gated channels have extracellular or intracellular domain receptors where the ligand will bind, which will induce a conformational change causing the channel to open or close (usually opens). These channels and mechanisms are all regulated via expression of genes. Most of these mechanisms are currently under research and belong to the field of molecular biology. The complexity of this subject is enormous, and to stay true to the purpose of this page it will not be discussed here, however if you are interested please see the reference below.[29] As you can see in the table below, which displays the major ion currents, their subunit proteins, some of their controlling genes, and the action potential phase where they are active everything in this mechanism is controlled through a hierarchy with gene expression at the head. Some of the most important ion channels involved in cardiac action potential are described briefly below.

Funny channels

Excitatory cells have the so-called pacemaker channels of the HCN family channels, Hyperpolarization-activated, Cyclic Nucleotide-gated channels. These poorly selective cation channels conduct more current as the membrane potential becomes more negative, or hyperpolarized. They conduct both potassium and sodium ions. The activity of these channels in the SAN cells causes the membrane potential to slowly become more positive (depolarize). They are the so-called "funny" channels and are responsible for the phase 4 diastolic depolarization.[7]

The fast Na+ channel

Main article: sodium channel

The fast sodium channels are voltage-dependent and have a very important role in the cardiac action potential in contractile cells as explained above. When these channels open due to localized depolarization from neighboring cells, rapid influx of sodium follows, thus causing the depolarization to reach threshold and initiate an action potential. These channels have three main functions: they permit quick influx of sodium ions, keep potassium ions from leaving the cell, and prevent calcium ions from getting stuck in the channel and interfering with sodium’s influx into the cell.[30] The important thing to remember is that these channels cause action potential initiation in contractile cells.

Structurally these channels have a voltage sensitive gate that opens the channel in response to depolarization, however they also have an inactivation gate, which is slower to activate. This gate is activated during the absolute refractory period, and is the reason why no action potentials can be initiated during that time. When the inactivation gate is activated the channel gate can be open (ions can enter), but no ions will be able to flow though because the inactivation gate is clogging the channel.

Potassium channels

Main article: Potassium channel

There are two main types of K+ channels but all have a basic common function: the creation of a transmembrane "leak" of potassium ions out of the cell (efflux), which is responsible for hyperpolarization.

The voltage gated (Kv) channels are activated by a specific depolarizing voltage change. They are located mainly inside the cellular membrane.[30]

The inward-rectifier channels (Kir) are gated by nucleotides and G proteins among other secondary messengers, most of which are located outside the cellular membrane.[31]

Calcium channels

Two voltage-dependent calcium channels play critical roles in the electro-physiology of cardiac muscle: L-type calcium channel ('L' for Long-lasting) and T-type calcium channels ('T' for Transient) voltage-gated calcium channels.

These channels respond to voltage changes across the membrane differently: L-type channels respond to higher membrane potentials, open more slowly, and remain open longer than T-type channels.

Because of these properties, L-type channels are important in sustaining an action potential, while T-type channels are important in initiating them.[19]

Because of their rapid kinetics, T-type channels are commonly found in cells undergoing rhythmic electrical behavior. For example, T-type channels are commonly found in some neuron cell bodies involved in rhythmic activity such as walking and breathing. These T-type calcium channels are also found in pacemaker cells, the sinoatrial node (SAN) and the atrioventricular node (AV).[19]


In heart physiology, autorhythmicity (also called automacity) is the ability of cardiac cells to depolarize spontaneously, i.e. without external electrical stimulation from the nervous system. This spontaneous depolarization is due to the special phase 4 as described above. Automaticity is controlled by the sinoatrial node (SAN), the so-called "Heart Pacemaker". Abnormalities in automaticity may result in rhythm disorders. Cells that can undergo the fastest spontaneous depolarization are the pacemaker cells, and set the heart rate, which have different action potential mechanisms than contractile cells of the heart. Electrical activity that originates from the SAN is propagated to the rest of the heart through the His-Purkinje network, the fastest conduction pathway. The electrical signal goes from the SAN, which stimulates the atrium to contract than moves to the AV node. There is a slight delay here known as the AV node delay (LINK), which allows the ventricle to fully fill with blood before contraction. The signal is than propagated down through the bundle of His to the Purkinje fibers at the apex of the heart, causing the ventricle to contract. This is the electrical conduction system of the heart.

This entire network of cells operate as latent pacemakers, meaning they have the ability to take over rhythm control if the SAN pacemaker cells should fail. But the conduction of action potentials and overall contraction rhythm will be slower than previously when the original pacemaker cells were controlling the rhythm. The non-pacemaker cells take over control in a hierarchical order: AV node (40-60/min) takes over first, than must rely on the- His bundle - Purkinje cells (20-40/min), which is fast enough to maintain the patient alive in supine position until the emergency team arrives, however is not fast enough to sustain long-term life.[32]

Regulation by the autonomic nervous system

The depolarization rate and duration of the action potential in pacemaker cells is affected, but not controlled by the autonomic nervous system activity. Parasympathetic activity releases acetylcholine (ACh) which binds to M2 (muscarinic) receptors and, via the βγ subunit of a G protein, opens a special set of potassium channels. The result is an increase in potassium efflux, which hyperpolarizes the cell, making the resting potential more negative. This means that the pacemaker cells (phase 4) take longer to reach their threshold voltage, so it takes longer to initiate an action potential. In addition, activation of M2 receptors decreases cAMP in the cells, and this slows the opening of Na+ and Ca2+ "L" channels, which means it takes a longer time to reach threshold. The ultimate result of parasympathetic activity is a decrease in the firing rate of action potentials and the overall heart rate.[33]

Conversely, sympathetic stimulation via β1 receptors causes a G-protein-induced increase in cAMP (opens sodium and calcium channels), which tends to increase the funny current.,[34] and therefore increases the rate of depolarization. The increase in cAMP levels from sympathetic stimulation also facilitates the opening of calcium channels thereby increasing the rate of depolarization, and overall increasing the firing rate of action potentials and overall heart rate.[33]

See also


  1. ^ Purking fibers are small terminal fibers coming from the His bundle and present everywhere in the cardiac muscle as the little branches of a tree
  2. ^ The symbol g is the conductance of an ion channel


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  • Rudy, Yoram (March 2008). "Molecular Basis of Cardiac Action Potential Repolarization". Annals of the New York Academy of Sciences 1123 (Control and Regulation of Transport Phenomena in the Cardiac System): 113–8. doi:10.1196/annals.1420.013. 
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