![Action_potential_ventr_myocyte](https://upload.wikimedia.org/wikipedia/commons/c/cb/Action_potential_ventr_myocyte.gif)
The cardiac action potential is a brief change in voltage (
membrane potential
Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. That is, there is a difference in the energy required for electric charges ...
) across the
cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
of
heart cells. This is caused by the movement of charged atoms (called
ions
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conven ...
) between the inside and outside of the cell, through
proteins
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
called
ion channels
Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...
. The cardiac action potential differs from
action potentials
An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, c ...
found in other types of
electrically excitable cell
Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. That is, there is a difference in the energy required for electric charges ...
s, such as nerves. Action potentials also vary within the heart; this is due to the presence of different ion channels in different cells.
Unlike the
action potential
An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...
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 cell
350px, Image showing the cardiac pacemaker or SA node, the primary pacemaker within the electrical_conduction_system_of_the_heart">SA_node,_the_primary_pacemaker_within_the_electrical_conduction_system_of_the_heart.
The_muscle_contraction.htm ...
s, that have automatic action potential generation capability. In healthy hearts, these cells form the
cardiac pacemaker
350px, Image showing the cardiac pacemaker or SA node, the primary pacemaker within the electrical_conduction_system_of_the_heart">SA_node,_the_primary_pacemaker_within_the_electrical_conduction_system_of_the_heart.
The_muscle_contraction.htm ...
and are found in the
sinoatrial node
The sinoatrial node (also known as the sinuatrial node, SA node or sinus node) is an oval shaped region of special cardiac muscle in the upper back wall of the right atrium made up of cells known as pacemaker cells. The sinus node is approximat ...
in the right
atrium
Atrium may refer to:
Anatomy
* Atrium (heart), an anatomical structure of the heart
* Atrium, the genital structure next to the genital aperture in the reproductive system of gastropods
* Atrium of the ventricular system of the brain
* Pulmona ...
. 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 disc
Intercalated discs or lines of Eberth are microscopic identifying features of cardiac muscle. Cardiac muscle consists of individual heart muscle cells (cardiomyocytes) connected by intercalated discs to work as a single functional syncytium. By con ...
s 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.
![Shapes of the cardiac action potential in the heart](https://upload.wikimedia.org/wikipedia/commons/e/e2/Shapes_of_the_cardiac_action_potential_in_the_heart.svg)
Rate dependence of the action potential is a fundamental property of cardiac cells and alterations can lead to severe cardiac diseases including
cardiac arrhythmia
Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...
and sometimes sudden death.
Action potential activity within the heart can be recorded to produce an
electrocardiogram (ECG). This is a series of upward and downward spikes (labelled P, Q, R, S and T) that represent the depolarization (voltage becoming more positive) and repolarization (voltage becoming more negative) of the action potential in the
atria and
ventricles.
Overview
Similar to skeletal muscle, the
resting membrane potential A relatively static membrane potential which is usually referred to as the ground value for trans-membrane voltage.
The relatively static membrane potential of quiescent cells is called the resting membrane potential (or resting voltage), as oppo ...
(voltage when the cell is not electrically excited) of
ventricular cells is around −90 millivolts (mV; 1 mV = 0.001 V), i.e. the inside of the membrane is more negative than the outside. The main ions found outside the cell at rest are sodium (Na
+), and chloride (Cl
−), whereas inside the cell it is mainly potassium (K
+).
The action potential begins with the voltage becoming more positive; this is known as
depolarization
In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is esse ...
and is mainly due to the opening of
sodium channel
Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel ...
s that allow
Na+ to flow into the cell. After a delay (known as the
absolute refractory period
Refractoriness is the fundamental property of any object of autowave nature (especially excitable medium) not to respond on stimuli, if the object stays in the specific ''refractory state''. In common sense, refractory period is the characteris ...
), 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
In neuroscience, repolarization refers to the change in membrane potential that returns it to a negative value just after the depolarization phase of an action potential which has changed the membrane potential to a positive value. The repolarizat ...
. Another important ion is
calcium (Ca2+), which can be found inside the cell in the
sarcoplasmic reticulum
The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other Cell (biology), cells. The main function of the SR is to store calcium ions (Ca2+). Calcium in bio ...
(SR) where calcium is stored, and is also found outside of the cell. Release of Ca
2+ from the SR, via a process called
calcium-induced calcium release
Calcium-induced calcium release (CICR) describes a biological process whereby calcium is able to activate calcium release from intracellular Ca2+ stores (e.g., endoplasmic reticulum or sarcoplasmic reticulum). Although CICR was first proposed for ...
, is vital for the plateau phase of the action potential (see phase 2, below) and is a fundamental step in
cardiac excitation-contraction coupling Cardiac excitation-contraction coupling (Cardiac EC coupling) describes the series of events, from the production of an Cardiac action potential, electrical impulse (action potential) to the Muscle contraction, contraction of muscles in the heart. ...
.
There are important physiological differences between the
pacemaker cells
350px, Image showing the cardiac pacemaker or SA node, the primary pacemaker within the electrical_conduction_system_of_the_heart">SA_node,_the_primary_pacemaker_within_the_electrical_conduction_system_of_the_heart.
The_muscle_contraction.ht ...
of the
sinoatrial node
The sinoatrial node (also known as the sinuatrial node, SA node or sinus node) is an oval shaped region of special cardiac muscle in the upper back wall of the right atrium made up of cells known as pacemaker cells. The sinus node is approximat ...
, 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
Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...
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
In physics and electrical engineering, a conductor is an object or type of material that allows the flow of charge (electric current) in one or more directions. Materials made of metal are common electrical conductors. Electric current is gener ...
muscle cells
A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a mus ...
of the heart to generate spontaneous cardiac action potentials. Automaticity can be normal or abnormal, caused by temporary
ion channel
Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...
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
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
.
Phases
![Currents responsible for the cardiac action potential](https://upload.wikimedia.org/wikipedia/commons/c/ce/Currents_responsible_for_the_cardiac_action_potential.png)
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
Diastole ( ) is the relaxed phase of the cardiac cycle when the chambers of the heart are re-filling with blood. The contrasting phase is systole when the heart chambers are contracting. Atrial diastole is the relaxing of the atria, and ventric ...
. In the standard non-pacemaker cell the voltage during this phase is more or less constant, at roughly -90 mV.
The
resting membrane potential A relatively static membrane potential which is usually referred to as the ground value for trans-membrane voltage.
The relatively static membrane potential of quiescent cells is called the resting membrane potential (or resting voltage), as oppo ...
results from the flux of ions having flowed into the cell (e.g. sodium and calcium), the flux of ions having flowed out of the cell (e.g. potassium, chloride and bicarbonate), as well as the flux of ions generated by the different membrane pumps, being perfectly balanced.
The activity of these
pumps
A pump is a device that moves fluids (liquids or gases), or sometimes slurries, by mechanical action, typically converted from electrical energy into hydraulic energy. Pumps can be classified into three major groups according to the method they u ...
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 electrochemichal equilibrium (e.g. sodium and calcium). 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, intrically linked to the first, is to keep the intracellular concentration more or less constant, and in this case to reestablish 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 (though as the potassium is mostly at the electrochemical equilibrium, its chemical gradient will naturally reequilibrate itself opposite to the electrical gradient, without the need for an active transport mechanism).
For example, the
sodium (Na+) and
potassium (K+) ions are maintained by the
sodium-potassium pump which uses energy (in the form of
adenosine triphosphate (ATP)) to move three Na
+ out of the cell and two K
+ into the cell. Another example is the
sodium-calcium exchanger
The sodium-calcium exchanger (often denoted Na+/Ca2+ exchanger, exchange protein, or NCX) is an antiporter membrane protein that removes calcium from cells. It uses the energy that is stored in the electrochemical gradient of sodium (Na+) by al ...
which removes one Ca
2+ 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 In a biological membrane, the reversal potential is the membrane potential at which the direction of ionic current reverses. At the reversal potential, there is no net flow of ions from one side of the membrane to the other. For channels that are pe ...
and can be calculated using the
Goldman-Hodgkin-Katz voltage equation.
However,
pacemaker cells
350px, Image showing the cardiac pacemaker or SA node, the primary pacemaker within the electrical_conduction_system_of_the_heart">SA_node,_the_primary_pacemaker_within_the_electrical_conduction_system_of_the_heart.
The_muscle_contraction.ht ...
are never at rest. In these cells, phase 4 is also known as the
pacemaker potential
In the pacemaking cells of the heart (e.g., the sinoatrial node), the pacemaker potential (also called the pacemaker current) is the slow, positive increase in voltage across the cell's membrane (the membrane potential) that occurs between the end ...
. During this phase, the membrane potential slowly becomes more positive, until it reaches a set value (around -40 mV; known as the threshold potential) 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 (Hyperpolarization-activated cyclic nucleotide-gated). These channels open at very negative voltages (i.e. immediately after phase 3 of the previous action potential; see below) 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
The pacemaker current (or I''f'', or IK''f'', also referred to as the funny current) is an electric current in the heart that flows through the HCN channel or pacemaker channel. Such channels are important parts of the electrical conduction system ...
(see below).
Another hypothesis regarding the pacemaker potential is the 'calcium clock'. Calcium is released from the
sarcoplasmic reticulum
The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other Cell (biology), cells. The main function of the SR is to store calcium ions (Ca2+). Calcium in bio ...
within the cell. This calcium then increases activation of the
sodium-calcium exchanger
The sodium-calcium exchanger (often denoted Na+/Ca2+ exchanger, exchange protein, or NCX) is an antiporter membrane protein that removes calcium from cells. It uses the energy that is stored in the electrochemical gradient of sodium (Na+) by al ...
resulting in the increase in membrane potential (as a +3 charge is being brought into the cell (by the 3Na
+) but only a +2 charge is leaving the cell (by the Ca
2+) therefore there is a net charge of +1 entering the cell). This calcium is then pumped back into the cell and back into the SR via calcium pumps (including the
SERCA SERCA, or sarco/endoplasmic reticulum Ca2+-ATPase, or SR Ca2+-ATPase, is a calcium ATPase-type P-ATPase. Its major function is to transport calcium from the cytosol into the sarcoplasmic reticulum.
Function
SERCA is a P-type ATPase. It resides i ...
).
Phase 0
This phase consists of a rapid, positive change in voltage across the cell membrane (
depolarization
In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is esse ...
) 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 (i.e. ventricular cells), this is produced predominantly by the activation of
Na+ channels, which increases the membrane conductance (flow) of Na
+ (g
Na). These channels are activated when an action potential arrives from a neighbouring cell, through
gap junctions
Gap junctions are specialized intercellular connections between a multitude of animal cell-types. They directly connect the cytoplasm of two cells, which allows various molecules, ions and electrical impulses to directly pass through a regulate ...
. When this happens, the voltage within the cell increases slightly. If this increased voltage reaches the
threshold potential
In electrophysiology, the threshold potential is the critical level to which a membrane potential must be depolarized to initiate an action potential. In neuroscience, threshold potentials are necessary to regulate and propagate signaling in both ...
(approximately −70 mV) 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
In physiology, the all-or-none law (sometimes the all-or-none principle or all-or-nothing law) is the principle that if a single nerve fibre is stimulated, it will always give a maximal response and produce an electrical impulse of a single ampl ...
. The influx of
calcium ions
Calcium ions (Ca2+) contribute to the physiology and biochemistry of organisms' cells. They play an important role in signal transduction pathways, where they act as a second messenger, in neurotransmitter release from neurons, in contraction of ...
(Ca
2+) through
L-type calcium channel
The L-type calcium channel (also known as the dihydropyridine channel, or DHP channel) is part of the high-voltage activated family of voltage-dependent calcium channel.
"L" stands for long-lasting referring to the length of activation. This c ...
s also constitutes a minor part of the depolarisation effect. The slope of phase 0 on the action potential waveform (see figure 2) represents the maximum rate of voltage change of the cardiac action potential and is known as dV/dt
max.
In pacemaker cells (e.g.
sinoatrial node 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
In the pacemaking cells of the heart (e.g., the sinoatrial node), the pacemaker potential (also called the pacemaker current) is the slow, positive increase in voltage across the cell's membrane (the membrane potential) that occurs between the end ...
(phase 4) 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.
[Santana, L.F., Cheng, E.P. and Lederer, J.W. (2010a) 'How does the shape of the cardiac action potential control calcium signaling and contraction in the heart?', 49(6).]
Phase 1
This phase begins with the rapid inactivation of the Na
+ channels by the inner gate (inactivation gate), reducing the movement of sodium into the cell. At the same time potassium channels (called I
to1) 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
Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. That is, there is a difference in the energy required for electric charges ...
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 (I
ks) allow potassium to leave the cell while L-type calcium channels (activated by the influx of sodium during phase 0) allow the movement of calcium ions into the cell. These calcium ions bind to and open more calcium channels (called ryanodine receptors) 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 (from the depolarisation of phase 0) 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 Ca
2+ influx as well as Na
+/Ca
2+ exchangers contributing to depolarisation.
This phase is responsible for the large duration of the action potential and is important in preventing irregular heartbeat (cardiac arrhythmia).
There is no plateau phase present in pacemaker action potentials.
Phase 3
During phase 3 (the "rapid repolarization" phase) of the action potential, the L-type
Ca2+ channels close, while the
slow delayed rectifier (I
Ks)
K+ channels remain open as more potassium leak channels open. This ensures a net outward positive current, corresponding to negative change in
membrane potential
Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. That is, there is a difference in the energy required for electric charges ...
, thus allowing more types of K
+ channels to open. These are primarily the
rapid delayed rectifier K
+ channels (I
Kr) and the
inwardly rectifying K
+ current, I
K1.
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 I
K1 remains conducting throughout phase 4, which helps to set the resting membrane potential
Ionic pumps as discussed above, like the
sodium-calcium exchanger
The sodium-calcium exchanger (often denoted Na+/Ca2+ exchanger, exchange protein, or NCX) is an antiporter membrane protein that removes calcium from cells. It uses the energy that is stored in the electrochemical gradient of sodium (Na+) by al ...
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 the heart muscles relax.
In the sinoatrial node, this phase is also due to the closure of the L-type calcium channels, preventing inward flux of Ca
2+ and the opening of the rapid delayed rectifier potassium channels (I
Kr).
Refractory period
Cardiac cells have two
refractory periods, the first from the beginning of phase 0 until part way through phase 3; this is known as the absolute refractory period during which it is impossible for the cell to produce 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 to produce another action potential.
These two refractory periods are caused by changes in the states of
sodium
Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable iso ...
and
potassium channels
Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of cel ...
. The rapid
depolarization
In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is esse ...
of the cell, during phase 0, causes the membrane potential to approach sodium's
equilibrium potential In a biological membrane, the reversal potential is the membrane potential at which the direction of ionic current reverses. At the reversal potential, there is no net flow of ions from one side of the membrane to the other. For channels that are pe ...
(i.e. the membrane potential at which sodium is no longer drawn into or out of the cell). As the membrane potential becomes more positive, the sodium channels then close and lock, this is known as the "inactivated" state. During this state the channels 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 makes the membrane potential more negative (i.e. it is hyperpolarised), this resets the sodium channels; opening the inactivation gate, but still leaving the channel closed. Because some of the voltage-gated sodium ion channels have recovered and the voltage-gated potassium ion channels remain open, it is possible to initiate another action potential if the stimulus is stronger than a stimulus which can fire an action potential when the membrane is at rest.
Gap junctions
Gap junction
Gap junctions are specialized intercellular connections between a multitude of animal cell-types. They directly connect the cytoplasm of two cells, which allows various molecules, ions and electrical impulses to directly pass through a regulate ...
s allow the action potential to be transferred from one cell to the next (they are said to ''electrically couple'' neighbouring
cardiac cells). They are made from the
connexin family of proteins, that form a pore through which ions (including Na
+, Ca
2+ and K
+) can pass. As potassium is highest within the cell, it is mainly potassium that passes through. This increased potassium in the neighbour cell causes the membrane potential to increase slightly, activating the sodium channels and initiating an action potential in this cell. (A brief chemical gradient driven efflux of Na+ through the
connexon
In biology, a connexon, also known as a connexin hemichannel, is an assembly of six proteins called connexins that form the pore for a gap junction between the cytoplasm of two adjacent cells. This channel allows for bidirectional flow of ions and ...
at peak depolarization causes the conduction of cell to cell depolarization, not potassium.) These connections allow for the rapid conduction of the action potential throughout the heart and are responsible for allowing all of the cells in the atria to contract together as well as all of the cells in the ventricles. Uncoordinated contraction of heart muscles is the basis for arrhythmia and heart failure.
Channels
Ion channels are proteins that change shape in response to different stimuli to either allow or prevent the movement of specific ions across a membrane. They are said to be selectively permeable. Stimuli, which can either come from outside the cell or from within the cell, can include the binding of a specific
molecule
A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...
to a receptor on the channel (also known as
ligand-gated ion channels
Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in res ...
) or a change in membrane potential around the channel, detected by a sensor (also known as
voltage-gated ion channels
Voltage-gated ion channels are a class of transmembrane proteins that form ion channels that are activated by changes in the electrical membrane potential near the channel. The membrane potential alters the conformation of the channel proteins, ...
) and can act to open or close the channel. The pore formed by an ion channel is aqueous (water-filled) and allows the ion to rapidly travel across the membrane. Ion channels can be selective for specific ions, so there are
Na+,
K+,
Ca2+, and
Cl− specific channels. They can also be specific for a certain charge of ions (i.e. positive or negative).
Each channel is coded by a set of DNA instructions that tell the cell how to make it. These instructions are known as a
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. Figure 3 shows the important ion channels involved in the cardiac action potential, the current (ions) that flows through the channels, their main protein subunits (building blocks of the channel), some of their controlling genes that code for their structure, and the phases that are active during the cardiac action potential. Some of the most important ion channels involved in the cardiac action potential are described briefly below.
HCN channels
Hyperpolarization-activated cyclic nucleotide-gated channels (HCN channels) are located mainly in pacemaker cells, these channels become active at very negative membrane potentials and allow for the passage of both Na
+ and K
+ into the cell (which is a movement is known as a funny current, I
f). These poorly selective, cation (positively charged ions) channels conduct more current as the membrane potential becomes more negative (hyperpolarised). The activity of these channels in the SAN cells causes the membrane potential to depolarise slowly and so they are thought to be responsible for the pacemaker potential. Sympathetic nerves directly affect these channels, resulting in an increased heart rate (see below).
The fast sodium channel
These
sodium channel
Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel ...
s are voltage-dependent, opening rapidly due to depolarization of the membrane, which usually occurs from neighboring cells, through gap junctions. They allow for a rapid flow of sodium into the cell, depolarizing the membrane completely and initiating an action potential. As the membrane potential increases, these channels then close and lock (become inactive). Due to the rapid influx sodium ions (steep phase 0 in action potential waveform) activation and inactivation of these channels happens almost at exactly the same time. During the inactivation state, Na
+ cannot pass through (absolute refractory period). However they begin to recover from inactivation as the membrane potential becomes more negative (relative refractory period).
Potassium channels
The two main types of potassium channels in cardiac cells are inward rectifiers and voltage-gated potassium channels.
Inwardly rectifying potassium channels (K
ir) favour the flow of K
+ into the cell. This influx of potassium, however, is larger when the membrane potential is more negative than the
equilibrium potential In a biological membrane, the reversal potential is the membrane potential at which the direction of ionic current reverses. At the reversal potential, there is no net flow of ions from one side of the membrane to the other. For channels that are pe ...
for K
+ (~-90 mV). As the membrane potential becomes more positive (i.e. during cell stimulation from a neighbouring cell), the flow of potassium into the cell via the K
ir decreases. Therefore, K
ir is responsible for maintaining the resting membrane potential and initiating the depolarization phase. However, as the membrane potential continues to become more positive, the channel begins to allow the passage of K
+ ''out'' of the cell. This outward flow of potassium ions at the more positive membrane potentials means that the K
ir can also aid the final stages of repolarisation.
The
voltage-gated potassium channel
Voltage-gated potassium channels (VGKCs) are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized ce ...
s (K
v) are activated by depolarization. The currents produced by these channels include the transient out potassium current
''I''to1. This current has two components. Both components activate rapidly, but ''I''
to,fast inactivates more rapidly than ''I''
to, slow. These currents contribute to the early repolarization phase (phase 1) of the action potential.
Another form of voltage-gated potassium channels are the delayed rectifier potassium channels. These channels carry potassium currents which are responsible for the plateau phase of the action potential, and are named based on the speed at which they activate: slowly activating ''I''
Ks, rapidly activating ''I''
Kr and ultra-rapidly activating ''I''
Kur.
Calcium channels
There are two
voltage-gated calcium channels
Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (''e.g.'', muscle, glial cells, neurons, etc.) with a permeabili ...
within cardiac muscle:
L-type calcium channel
The L-type calcium channel (also known as the dihydropyridine channel, or DHP channel) is part of the high-voltage activated family of voltage-dependent calcium channel.
"L" stands for long-lasting referring to the length of activation. This c ...
s ('L' for Long-lasting) and
T-type calcium channel
T-type calcium channels are low voltage activated calcium channels that become inactivated during cell membrane hyperpolarization but then open to depolarization. The entry of calcium into various cells has many different physiological responses a ...
s ('T' for Transient, i.e. short). L-type channels are more common and are most densely populated within the t-tubule membrane of ventricular cells, whereas the T-type channels are found mainly within
atrial
The atrium ( la, ātrium, , entry hall) is one of two upper chambers in the heart that receives blood from the circulatory system. The blood in the atria is pumped into the heart ventricles through the atrioventricular valves.
There are two atr ...
and
pacemaker cells
350px, Image showing the cardiac pacemaker or SA node, the primary pacemaker within the electrical_conduction_system_of_the_heart">SA_node,_the_primary_pacemaker_within_the_electrical_conduction_system_of_the_heart.
The_muscle_contraction.ht ...
, but still to a lesser degree than L-type channels.
These channels respond to voltage changes across the membrane differently: L-type channels are activated by more positive membrane potentials, take longer to open and remain open longer than T-type channels. This means that the T-type channels contribute more to depolarization (phase 0) whereas L-type channels contribute to the plateau (phase 2).
Conduction system
![Conductionsystemoftheheart](https://upload.wikimedia.org/wikipedia/commons/d/d5/Conductionsystemoftheheart.png)
In the
heart's conduction system electrical activity that originates from the sinoatrial node is propagated via the His-Purkinje network, the fastest conduction pathway within the heart. The electrical signal travels from the
sinoatrial node (SAN), which stimulates the
atria to contract, to the
atrioventricular node (AVN) which slows down conduction of the action potential, from the atria to the
ventricles. This delay allows the ventricles to fully fill with blood before contraction. The signal then passes down through a bundle of fibres called the
bundle of His
The bundle of His (BH) or His bundle (HB) ( "hiss"Medical Terminology for Health Professions, Spiral bound Version'. Cengage Learning; 2016. . pp. 129–.) is a collection of heart muscle cells specialized for electrical conduction. As part of t ...
, located between the ventricles, and then to the
purkinje fibers
The Purkinje fibers (; often incorrectly ; Purkinje tissue or subendocardial branches) are located in the inner ventricular walls of the heart, just beneath the endocardium in a space called the subendocardium. The Purkinje fibers are specia ...
at the bottom (apex) of the heart, causing ventricular contraction.
Other than the SAN, the AVN and purkinje fibres also have pacemaker activity and can therefore spontaneously generate an action potential. However, these cells usually do not depolarize spontaneously, simply because, action potential production in the SAN is faster. This means that before the AVN or purkinje fibres reach the threshold potential for an action potential, they are depolarized by the oncoming impulse from the SAN This is called "overdrive suppression".
Pacemaker activity of these cells is vital, as it means that if the SAN were to fail, then the heart could continue to beat, albeit at a lower rate (AVN= 40-60 beats per minute, purkinje fibres = 20-40 beats per minute). These pacemakers will keep a patient alive until the emergency team arrives.
An example of premature ventricular contraction, is the classic
athletic heart syndrome
Athletic heart syndrome (AHS) is a non-disease, pathological condition commonly seen in sports medicine in which the human heart is cardiomegaly, enlarged, and the resting heart rate is bradycardia, lower than normal.
The athlete's heart is asso ...
. Sustained training of athletes causes a cardiac adaptation where the resting SAN rate is lower (sometimes around 40 beats per minute). This can lead to
atrioventricular block
Atrioventricular block (AV block) is a type of heart block that occurs when the electrical signal traveling from the atria, or the upper chambers of the heart, to ventricles, or the lower chambers of the heart, is impaired. Normally, the sinoatr ...
, where the signal from the SAN is impaired in its path to the ventricles. This leads to uncoordinated contractions between the atria and ventricles, without the correct delay in between and in severe cases can result in sudden death.
Regulation by the autonomic nervous system
The speed of action potential production in pacemaker cells is affected, but not controlled by the
autonomic nervous system
The autonomic nervous system (ANS), formerly referred to as the vegetative nervous system, is a division of the peripheral nervous system that supplies viscera, internal organs, smooth muscle and glands. The autonomic nervous system is a control ...
.
The
sympathetic nervous system
The sympathetic nervous system (SNS) is one of the three divisions of the autonomic nervous system, the others being the parasympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of th ...
(nerves dominant during the body's
fight-or-flight response
The fight-or-flight or the fight-flight-or-freeze response (also called hyperarousal or the acute stress response) is a physiological reaction that occurs in response to a perceived harmful event, attack, or threat to survival. It was first des ...
) increase heart rate (positive
chronotropy
Chronotropic effects (from ''chrono-'', meaning time, and ''tropos'', "a turn") are those that change the heart rate.
Chronotropic drugs may change the heart rate and rhythm by affecting the electrical conduction system of the heart and the ne ...
), by decreasing the time to produce an action potential in the SAN. Nerves from the
spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spi ...
release a molecule called
noradrenaline
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
, which binds to and activates receptors on the pacemaker cell membrane called
β1 adrenoceptors. This activates a protein, called a G
s-protein (s for stimulatory). Activation of this G-protein leads to increased levels of
cAMP
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
in the cell (via the
cAMP pathway). cAMP binds to the HCN channels (see above), increasing the funny current and therefore increasing the rate of depolarization, during the pacemaker potential. The increased cAMP also increases the opening time of L -type calcium channels, increasing the Ca
2+ current through the channel, speeding up phase 0.
The
parasympathetic nervous system
The parasympathetic nervous system (PSNS) is one of the three divisions of the autonomic nervous system, the others being the sympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of ...
(
nerve
A nerve is an enclosed, cable-like bundle of nerve fibers (called axons) in the peripheral nervous system.
A nerve transmits electrical impulses. It is the basic unit of the peripheral nervous system. A nerve provides a common pathway for the e ...
s dominant while the body is resting and digesting) decreases heart rate (negative
chronotropy
Chronotropic effects (from ''chrono-'', meaning time, and ''tropos'', "a turn") are those that change the heart rate.
Chronotropic drugs may change the heart rate and rhythm by affecting the electrical conduction system of the heart and the ne ...
), by increasing the time taken to produce an action potential in the SAN. A nerve called the
vagus nerve
The vagus nerve, also known as the tenth cranial nerve, cranial nerve X, or simply CN X, is a cranial nerve that interfaces with the parasympathetic control of the heart, lungs, and digestive tract. It comprises two nerves—the left and right ...
, that begins in the brain and travels to the sinoatrial node, releases a
molecule
A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...
called
acetylcholine (ACh) which binds to a receptor located on the outside of the pacemaker cell, called an
M2 muscarinic receptor
The muscarinic acetylcholine receptor M2, also known as the cholinergic receptor, muscarinic 2, is a muscarinic acetylcholine receptor that in humans is encoded by the ''CHRM2'' gene. Multiple alternatively spliced transcript variants have been ...
. This activates a
Gi-protein (I for inhibitory), which is made up of 3 subunits (α, β and γ) which, when activated, separate from the receptor. The β and γ subunits activate a special set of potassium channels, increasing potassium flow out of the cell and decreasing membrane potential, meaning that the pacemaker cells take longer to reach their threshold value. The G
i-protein also inhibits the cAMP pathway therefore reducing the sympathetic effects caused by the spinal nerves.
Clinical significance
Antiarrhythmic drugs are used to regulate
heart rhythms that are too fast. Other drugs used to influence the cardiac action potential include
sodium channel blocker
Sodium channel blockers are drugs which impair the conduction of sodium ions (Na+) through sodium channels.
Extracellular
The following naturally-produced substances block sodium channels by binding to and occluding the extracellular pore opening ...
s,
beta blocker
Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage cardiac arrhythmia, abnormal heart rhythms, and to protect the heart from a second myocardial infarction, heart attack after a first heart ...
s,
potassium channel blocker
Potassium channel blockers are agents which interfere with conduction through potassium channels.
Medical uses
Arrhythmia
Potassium channel blockers used in the treatment of cardiac arrhythmia are classified as class III antiarrhythmic age ...
s, and
calcium channel blocker
Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium () through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as ...
s.
References
Bibliography
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External links
Interactive animationillustrating the generation of a cardiac action potential
of cardiac action potential and other generic action potentials
{{Cardiovascular physiology
Cardiac electrophysiology
Action potentials