Cardiac action potential
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2008-07-06T17:04:39Z
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/* Phases of the cardiac action potential */
The '''cardiac action potential''' is a specialized [[action potential]] in the [[heart]], with unique properties necessary for function of the [[electrical conduction system of the heart]].
The cardiac action potential differs significantly in different portions of the heart. This differentiation of the action potentials allows the different electrical characteristics of the different portions of the heart. For instance, the specialized conduction tissue of the heart has the special property of [[depolarizing]] without any external influence. This is known as [[cardiac muscle automaticity]].
The electrical activity of the specialized conduction tissues are not apparent on the surface [[electrocardiogram]] (ECG). This is due to the relatively small mass of these tissues compared to the [[myocardium]].
==Overview==
{| border="1" cellpadding="1" cellspacing="1" align="right" width="30%"
|+ '''Intra- and extracellular [[ion]] concentrations ([[mole (unit)|mmol]]/[[Litre|L]])'''
|-----
! style="background:#efefef;" width="50px" | Element
! style="background:#efefef;" width="25px" | Ion
! style="background:#efefef;" width="50px" | Extracellular
! style="background:#efefef;" width="50px" | Intracellular
! style="background:#efefef;" width="50px" | Ratio
|-----
| Sodium || Na<sup>+</sup> || 135 - 145 || 10 || 14:1
|-----
| Potassium || K<sup>+</sup> || 3.5 - 5.0 || 155 || 1:16
|-----
| Chloride || Cl<sup>-</sup> || 95 - 110 || 20 - 30 || 4:1
|-----
| Calcium
| Ca<sup>2+</sup>
| 2
| 10<sup>-4</sup>
| 2 x 10<sup>4</sup>
|-----
| style="border-bottom:3px solid grey;" colspan="5" align="center" | <font size="-2">''Although intracellular Ca<sup>2+</sup> content is about 2 mM, most of this is bound or sequestered in intracellular organelles (mitochondria and sarcoplasmic reticulum).''</font>
|}
Cardiac muscle has some similarities to skeletal muscle, as well as important unique properties. Like skeletal myocytes (and axons for that matter), a given cardiac myocyte has a negative [[membrane potential]] when at rest. A notable difference between skeletal and cardiac myocytes is how each elevates the myoplasmic Ca<sup>2+</sup> to induce contraction. When skeletal muscle is stimulated by somatic motor axons, influx of Na<sup>+</sup> quickly depolarizes the skeletal myocyte and triggers calcium release from the sarcoplasmic reticulum. In cardiac myocytes, the release of Ca<sup>2+</sup> from the [[sarcoplasmic reticulum]] is induced by Ca<sup>2+</sup> 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 Ca<sup>2+</sup> concentration causing [[muscle contraction]]. In both muscle types, after a delay, (the [[Refractory period (cardiac)|absolute refractory period]]), [[Potassium channels]] reopen and the resulting flow of K<sup>+</sup> out of the cell causes [[repolarization]] to the resting state. 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).
Note that there are important physiological differences between nodal cells and ventricular cells; the specific differences in ion channels and mechanisms of polarization give rise to unique properties of SA node cells, most importantly the spontaneous depolarizations ([[cardiac muscle automaticity]]) necessary for the SA node's [[cardiac pacemaker|pacemaker]] activity.
==Major currents==
{| border="1" cellpadding="10" cellspacing="0" align="center"
|+ '''Major currents during the cardiac ventricular action potential'''
|-----
! style="background:#efefef;" width="60px" | Ion
! style="background:#efefef;" width="60px" | Current
! style="background:#efefef;" width="100px" | α subunit protein
! style="background:#efefef;" width="200px" | α subunit gene
! style="background:#efefef;" width="100px" | Phase / role
|-----
| Na<sup>+</sup> || ''I''<sub>Na</sub> || Na<sub>V</sub>1.5 || {{Gene|SCN5A}} || 0
|-----
| Ca<sup>2+</sup> || ''I''<sub>Ca(L)</sub> || Ca<sub>V</sub>1.2 || {{Gene|CACNA1C}} || 0-2
|-----
| K<sup>+</sup> || ''I''<sub>to1</sub> || K<sub>V</sub>4.2/4.3 || {{Gene|KCND2}}/{{Gene|KCND3}} || 1, notch
|-----
| K<sup>+</sup> || ''I''<sub>Ks</sub> || K<sub>V</sub>7.1 || {{Gene|KCNQ1}} || 2,3
|-----
| K<sup>+</sup> || ''I''<sub>Kr</sub> || K<sub>V</sub>11.1 ([[hERG]]) || {{Gene|KCNH2}} || 3
|-----
| K<sup>+</sup> || ''I''<sub>K1</sub> || [[Inward-rectifier potassium ion channel|K<sub>ir</sub>2.1/2.2/2.3]] || {{Gene|KCNJ2}}/{{Gene|KCNJ12}}/{{Gene|KCNJ4}} || 3,4
|-----
| Na<sup>+</sup>, Ca<sup>2+</sup> || ''I''<sub>NaCa</sub> || [[Sodium-calcium exchanger|3Na<sup>+</sup>-1Ca<sup>2+</sup>-exchanger]] || ''NCX1'' ({{Gene|SLC8A1}}) || ion homeostasis
|-----
| Na<sup>+</sup>, K<sup>+</sup> || ''I''<sub>NaK</sub> || [[Na+/K+-ATPase|3Na<sup>+</sup>-2K<sup>+</sup>-ATPase]] || ''ATP1A'' || ion homeostasis
|-----
| Ca<sup>2+</sup> || ''I''<sub>pCa</sub> || [[Calcium ATPase|Ca<sup>2+</sup>-transporting ATPase]] || ''ATP1B'' || ion homeostasis
|}
===Calcium channels===
Two [[voltage-dependent calcium channel]]s play critical roles in the physiology of [[cardiac muscle]]: [[L-type calcium channel]] ('L' for Long-lasting) and [[T-type calcium channel]]s ('T' for Transient) voltage-gated calcium channels.
These channels respond differently to voltage changes across the membrane: 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.
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 (i.e. sinoatrial node and atrioventricular node) of the heart which control the heart beat.
L-type channels are the targets of a class of drugs called dihydropyridines which block the currents produced by these channels.
==Resting membrane potential==
The [[resting membrane potential]] is caused by the difference in ionic concentrations and conductances across the membrane of the cell 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 [[potassium|K<sup>+</sup>]] and relatively impermeable to other ions. The resting membrane potential is therefore dominated by the K<sup>+</sup> [[equilibrium potential]] according to the K<sup>+</sup> gradient across the cell membrane. The membrane potential can be calculated using the [[Goldman equation|Goldman-Hodgkin-Katz voltage equation]]. The maintenance of this electrical gradient is due to various ion pumps and exchange mechanisms, including the [[sodium|Na<sup>+</sup>]]-K<sup>+</sup> [[NaKATPase|ion exchange pump]], the Na<sup>+</sup>-[[calcium|Ca<sup>2+</sup>]] exchanger current and the I<sub>K1</sub> [[Inward-rectifier potassium ion channel|inwardly rectifying]] K<sup>+</sup> current.
Intracellularly (within the cell), K<sup>+</sup> is the principal [[cation]], and [[phosphate]] and the [[conjugate acid|conjugate base]]s of [[organic acid]]s are the dominant [[anion]]s. Extracellularly (outside the cell), [[sodium|Na<sup>+</sup>]] and [[chloride|Cl<sup>-</sup>]] predominate.
'''Bold text'''==Phases of the cardiac action potential==
[[Image:Action_potential.png|thumb|275px|The cardiac action potential has five phases.]]
The standard model used to understand the cardiac action potential is the action potential of the ventricular [[myocyte]]. The action potential has 5 phases (numbered 0-4). Phase 4 is the resting membrane potential, and describes the membrane potential when the cell is not being stimulated.
Once the cell is electrically stimulated (typically by an electric current from an adjacent cell), it begins a sequence of actions involving the influx and efflux of multiple [[cation]]s and [[anion]]s that together produce the [[action potential]] of the cell, propagating the electrical stimulation to the cells that lie adjacent to it. In this fashion, an electrical stimulation is conducted from one cell to all the cells that are adjacent to it, to all the cells of the heart.
===Phase 4===
''Phase 4'' is the [[resting membrane potential]]. This is the period that the cell remains in until it is stimulated by an external electrical stimulus (typically an adjacent cell). This phase of the action potential is associated with [[diastole]] of the chamber of the heart.
In addition to stimulus from adjacent cells, certain cells of the heart have the ability to undergo ''spontaneous depolarization'', in which an action potential is generated without any influence from nearby cells. This is also known as [[cardiac muscle automaticity]].
===Phase 0===
''Phase 0'' is the rapid depolarization phase. The [[slope]] of phase 0 represents the maximum rate of depolarization of the cell and is known as V<sub>max</sub>. This phase is due to the opening of the fast Na<sup>+</sup> [[ion channel|channels]] causing a rapid increase in the membrane conductance to Na<sup>+</sup> (''G''<sub>Na</sub>) and thus a rapid influx of Na<sup>+</sup> ions (''I''<sub>Na</sub>) into the cell; a Na<sup>+</sup> current.
The ability of the cell to open the fast Na<sup>+</sup> channels during phase 0 is related to the membrane potential at the moment of excitation. If the membrane potential is at its baseline (about -85 mV), all the fast Na<sup>+</sup> channels are closed, and excitation will open them all, causing a large influx of Na<sup>+</sup> ions. If, however, the membrane potential is less negative, some of the fast Na<sup>+</sup> channels will be in an inactivated state insensitive to opening, thus causing a lesser response to excitation of the cell membrane and a lower V<sub>max</sub>. For this reason, if the resting membrane potential becomes too positive, the cell may not be excitable, and conduction through the heart may be delayed, increasing the risk for [[cardiac arrhythmia|arrhythmias]].
====The fast Na<sup>+</sup> channel====
The fast [[sodium channel]] can be modeled as being controlled by a number of ''gates''. Each gate (or gating variable) can attain a value between 1 (fully open) and 0 (fully closed). The product of all the gates denotes the percentage of channels available to conduct [[sodium|Na<sup>+</sup>]]. Following the model of [[Hodgkin–Huxley model|Hodgkin and Huxley]], the sodium channel contains three gates: ''m'', ''h'', and ''j''. In the resting state, the ''m'' gate is closed (zero) and the ''h'' and ''j'' gates are open (one). Hence, the product denoting the percentage of conducting channels is also zero. Upon electrical stimulation of the cell, the ''m'' gate opens quickly while simultaneously the ''h'' and ''j'' gates close more slowly. For a brief period of time, all gates are open (''i.e.'' non-zero) and Na<sup>+</sup> can enter the cell following its [[electrochemical gradient]]. If, as above, the resting membrane potential is too positive, the ''h'' or ''j'' gates may be considerably less than one, such that the product of ''m'', ''h'' and ''j'' becomes too small upon depolarization.
===Phase 1===
''Phase 1'' of the action potential occurs with the inactivation of the fast [[sodium channel|Na<sup>+</sup> channels]]. The transient net outward current causing the small downward deflection of the action potential is due to the movement of K<sup>+</sup> and Cl<sup>-</sup> ions, carried by the I<sub>to1</sub> and I<sub>to2</sub> currents, respectively. Particularly the I<sub>to1</sub> contributes to the "notch" of some ventricular cardiomyocyte action potentials.
It has been suggested that Cl<sup>-</sup> ions movement across the cell membrane during Phase I is as a result of the change in membrane potential, from K<sup>+</sup> efflux, and is not a contributory factor to the initial repolarisation ("notch").
===Phase 2===
This "plateau" phase of the cardiac action potential is sustained by a balance between inward movement of Ca<sup>2+</sup> (I<sub>Ca</sub>) through L-type [[Voltage-dependent calcium channel|calcium channels]] and outward movement of K<sup>+</sup> through the slow delayed rectifier [[potassium channels]], [[KvLQT1|I<sub>Ks</sub>]]. The [[sodium-calcium exchanger]] current, I<sub>Na,Ca</sub> and the [[Na-K pump|sodium/potassium pump]] current, I<sub>Na,K</sub> also play minor roles during phase 2.
===Phase 3===
During phase 3 of the action potential, the L-type [[voltage dependent calcium channel|Ca<sup>2+</sup> channels]] close, while the [[KvLQT1|slow delayed rectifier]] (I<sub>Ks</sub>) [[potassium channels|K<sup>+</sup> channels]] are still open. This ensures a net outward current, corresponding to negative change in [[membrane potential]], thus allowing more types of K<sup>+</sup> channels to open. These are primarily the [[HERG|rapid delayed rectifier]] K<sup>+</sup> channels (I<sub>Kr</sub>) and the [[Inward-rectifier potassium ion channel|inwardly rectifiyng]] K<sup>+</sup> current, I<sub>K1</sub>.
This net outward, positive current (equal to loss of positive charge from the cell) causes the cell to repolarize. The delayed rectifier K<sup>+</sup> channels close when the membrane potential is restored to about -80 to -85 mV, while I<sub>K1</sub> remains conducting throughout phase 4, contributing to set the resting membrane potential.
[[Image:Pacemaker_potential.svg|frame]]
==Automaticity== <!--Cardiac muscle automaticity redirects here-->
In the myocardium, automaticity is the ability of the cardiac muscles to depolarize spontaneously, i.e without external electrical stimulation from the nervous system. This spontaneous depolarization is due to the plasma membranes within the heart that have reduced permeability to potassium (K+) but still allow passive transfer of calcium ions, allowing a net charge to build. Automaticity is most often demonstrated in the [[sinoatrial node]], the so called "Pacemaker of the Heart." Abnormalities in automaticity result in rhythm changes.
===Location===
The cells that can undergo spontaneous depolarization the fastest are the primary pacemaker cells of the heart, and set the heart rate. Usually, these are cells in the [[SA node]] of the heart. Electrical activity that originates from the SA node is propagated to the rest of the heart. The fastest conduction of electrical activity is via the [[electrical conduction system of the heart]].
===Channels===
The mechanism of automaticity involves the so-called [[Ion channel#Diversity|pacemaker channels]] of the HCN family, [[Hyperpolarization]]-activated, [[Cyclic nucleotide|Cyclic Nucleotide]]-gated channels (see [[Funny current]]). These poorly selective cation channels conduct more current as the membrane potential becomes more negative, or hyperpolarized. They conduct both potassium and sodium. The activity of these channels in the SA node cells causes the membrane potential to slowly become more positive (depolarized) until, eventually, calcium channels are activated and an action potential is initiated.
===Abnormal automaticity===
The normal activity of the pacemaker cells of the heart is to spontaneously depolarize at a regular rhythm, generating the normal heart rate. Abnormal automaticity involves the abnormal spontaneous depolarization of cells of the heart. This typically causes [[cardiac arrhythmia|arrhythmias]] (irregular rhythms) in the heart.
In cases of [[heart block]], in which the activity of the primary pacemaker does not propagate to the rest of the heart, a latent pacemaker (also known as an escape pacemaker) will undergo spontaneous depolarization and create an action potential.
==See also==
* [[Electrical conduction system of the heart]]
* [[Action potential]]
* [[Antiarrhythmic agents]]
* [[Cardiac arrhythmia]]
* [[Cardiac pacemaker]]
* [[Resting membrane potential]]
* [[Ventricular action potential]]
==External links==
* [http://thevirtualheart.org/CAPindex.html Interactive animation] illustrating the generation of a cardiac action potential.
* [http://thevirtualheart.org/APindex.html Interactive mathematical models] of cardiac action potential and other generic action potentials.
{{Cardiovascular physiology}}
[[Category:Cardiac electrophysiology]]