Editing Cardiac action potential (section)

==Phases==
[[File:Currents responsible for the cardiac action potential.png|thumb|440x440px|Action potentials recorded from sheep atrial and ventricular cardiomyocytes with phases shown. Ion currents approximate to [[ventricular action potential]].]]
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.
[[File:CAP Waveform.jpg|thumb|440x440px|Figure 2a: Ventricular action potential (left) and sinoatrial node action potential (right) waveforms. The main ionic currents responsible for the phases are below (upwards deflections represent ions flowing out of cell, downwards deflection represents inward current).]]

===Phase 4===
In the ventricular myocyte, phase 4 occurs when the cell is at rest, in a period known as [[diastole]]. In the standard non-pacemaker cell the voltage during this phase is more or less constant, at roughly -90 mV.<ref name="santana 496" /> The [[resting membrane potential]] 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.{{cn|date=May 2025}}

The activity of these [[ion transporter|pumps]] serve two purposes. The first is to maintain the existence of the resting membrane potential by countering the depolarisation due to the leakage of ions not at the electrochemical equilibrium (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.{{cn|date=May 2025}}

The second purpose, intricately linked to the first, is to keep the intracellular concentration more or less constant, and in this case to re-establish the original chemical gradients, that is to force the sodium and calcium which previously flowed into the cell out of it, and the potassium which previously flowed out of the cell back into it (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).{{cn|date=May 2025}}

For example, the [[sodium|sodium (Na<sup>+</sup>)]] and [[potassium|potassium (K<sup>+</sup>)]] ions are maintained by the [[Na+/K+-ATPase|sodium-potassium pump]] which uses energy (in the form of [[Adenosine triphosphate|adenosine triphosphate (ATP)]]) to move three Na<sup>+</sup> out of the cell and two K<sup>+</sup> into the cell. Another example is the [[sodium-calcium exchanger]] which removes one Ca<sup>2+</sup> from the cell for three Na<sup>+</sup> into the cell.<ref>{{Cite journal |last=Morad M., Tung L. |year=1982 |title=Ionic events responsible for the cardiac resting and action potential |journal=The American Journal of Cardiology |volume=49 |issue=3 |pages=584–594 |doi=10.1016/s0002-9149(82)80016-7 |pmid=6277179}}</ref>

During this phase the membrane is most permeable to K<sup>+</sup>, which can travel into or out of cell through leak channels, including the inwardly rectifying potassium channel.<ref>{{Cite journal |last=Grunnet M |year=2010 |title=Repolarization of the cardiac action potential. Does an increase in repolarization capacity constitute a new anti-arrhythmic principle? |journal=Acta Physiologica |volume=198 |pages=1–48 |doi=10.1111/j.1748-1716.2009.02072.x |pmid=20132149 |doi-access=free}}</ref> Therefore, the resting membrane potential is mostly equal to K<sup>+</sup> [[Reversal potential|equilibrium potential]] and can be calculated using the [[goldman equation|Goldman-Hodgkin-Katz voltage equation]].{{cn|date=May 2025}}

However, [[pacemaker cells]] are never at rest. In these cells, phase 4 is also known as the [[pacemaker potential]]. During this phase, the membrane potential slowly becomes more positive, until it reaches a set value (around -40 mV; known as the threshold potential) or until it is depolarized by another action potential, coming from a neighboring cell.{{cn|date=May 2025}}

The pacemaker potential is thought to be due to a group of channels, referred to as [[HCN channel|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<sup>+</sup> and Na<sup>+</sup> 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]] (see below).<ref name="DiFrancesco funny" />

Another hypothesis regarding the pacemaker potential is the 'calcium clock'. Calcium is released from the [[sarcoplasmic reticulum]] within the cell. This calcium then increases activation of the [[sodium-calcium exchanger]] resulting in the increase in membrane potential (as a +3 charge is being brought into the cell (by the 3Na<sup>+</sup>) but only a +2 charge is leaving the cell (by the Ca<sup>2+</sup>) 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]]).<ref name="pmid21319337">{{Cite journal |vauthors=Joung B, Chen PS, Lin SF |date=March 2011 |title=The role of the calcium and the voltage clocks in sinoatrial node dysfunction |journal=Yonsei Medical Journal |volume=52 |issue=2 |pages=211–9 |doi=10.3349/ymj.2011.52.2.211 |pmc=3051220 |pmid=21319337}}</ref>

===Phase 0===
This phase consists of a rapid, positive change in voltage across the cell membrane ([[depolarization]]) lasting less than 2&nbsp;ms in ventricular cells and 10–20&nbsp;ms in [[Sinoatrial node|SAN]] cells.<ref>{{Cite journal |last=Shih |first=H T |date=1994-01-01 |title=Anatomy of the action potential in the heart. |journal=Texas Heart Institute Journal |volume=21 |issue=1 |pages=30–41 |issn=0730-2347 |pmc=325129 |pmid=7514060}}</ref> This occurs due to a net flow of positive charge into the cell.{{cn|date=May 2025}}

In non-pacemaker cells (i.e. ventricular cells), this is produced predominantly by the activation of [[sodium channels|Na<sup>+</sup> channels]], which increases the membrane conductance (flow) of Na<sup>+</sup> (g<sub>Na</sub>). These channels are activated when an action potential arrives from a neighbouring cell, through [[gap junctions]]. When this happens, the voltage within the cell increases slightly. If this increased voltage reaches the [[threshold potential]] (approximately −70&nbsp;mV) it causes the Na<sup>+</sup> channels to open. This produces a larger influx of sodium into the cell, rapidly increasing the voltage further to around +50&nbsp;mV,<ref name="santana 496 901" /> i.e. towards the Na<sup>+</sup> 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]].{{sfn|Purves et al.|2008|pp= 26–28}}{{sfn|Rhoades & Bell|2009|p=45}} The influx of [[Calcium|calcium ions]] (Ca<sup>2+</sup>) through [[L-type calcium channel]]s also constitutes a minor part of the depolarisation effect.<ref>{{Cite book |last=Boron |first=Walter F. |title=Medical physiology : a cellular and molecular approach |last2=Boulpaep |first2=Emile L. |others=Boron, Walter F.,, Boulpaep, Emile L. |year=2012 |isbn=9781437717532 |edition=Updated |location=Philadelphia, PA |pages=508 |oclc=756281854}}</ref> 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<sub>max</sub>.

In pacemaker cells (e.g. [[sinoatrial node|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]] (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.<ref name="santana 496">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).</ref>{{sfn|Sherwood|2012|p=311}}

===Phase 1===
This phase begins with the rapid inactivation of the Na<sup>+</sup> channels by the inner gate (inactivation gate), reducing the movement of sodium into the cell. At the same time potassium channels (called I<sub>to1</sub>) 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.<ref name="santana 496" />

There is no obvious phase 1 present in pacemaker cells.

===Phase 2===
This phase is also known as the "plateau" phase due to the [[membrane potential]] remaining almost constant, as the membrane slowly begins to repolarize. This is due to the near balance of charge moving into and out of the cell. During this phase [[KvLQT1|delayed rectifier potassium channels]] (I<sub>ks</sub>) 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.{{cn|date=May 2025}}

Calcium also activates chloride channels called I<sub>to2</sub>, which allow Cl<sup>−</sup> 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<sup>+</sup> outflux, Cl<sup>−</sup> influx as well as Na<sup>+</sup>/K<sup>+</sup> pumps contributing to repolarisation and Ca<sup>2+</sup> influx as well as Na<sup>+</sup>/Ca<sup>2+</sup> exchangers contributing to depolarisation.<ref name="Grunnet M 2010b 1–48">{{Cite journal |last=Grunnet M |year=2010b |title=Repolarization of the cardiac action potential. Does an increase in repolarization capacity constitute a new anti-arrhythmic principle? |journal=Acta Physiologica |volume=198 |pages=1–48 |doi=10.1111/j.1748-1716.2009.02072.x |pmid=20132149 |doi-access=free}}</ref><ref name="santana 496" /> 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 [[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]] 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<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 rectifying]] 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 -85 to -90 mV, while I<sub>K1</sub> remains conducting throughout phase 4, which helps to set the resting membrane potential<ref name="Kubo2005">{{Cite journal |last=Kubo |first=Y |last2=Adelman |first2=JP |last3=Clapham |first3=DE |last4=Jan |first4=LY |last5=Karschin |first5=A |last6=Kurachi |first6=Y |last7=Lazdunski |first7=M |last8=Nichols |first8=CG |last9=Seino |first9=S |last10=Vandenberg |first10=CA |display-authors=4 |year=2005 |title=International Union of Pharmacology. LIV. Nomenclature and molecular relationships of inwardly rectifying potassium channels |journal=Pharmacol Rev |volume=57 |issue=4 |pages=509–26 |doi=10.1124/pr.57.4.11 |pmid=16382105 |s2cid=11588492 |ref={{sfnref|Kubo et al.|2005}}}}</ref>

Ionic pumps as discussed above, like the [[sodium-calcium exchanger]] and the [[Na+/K+-ATPase|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.{{cn|date=May 2025}}

In the sinoatrial node, this phase is also due to the closure of the L-type calcium channels, preventing inward flux of Ca<sup>2+</sup> and the opening of the rapid delayed rectifier potassium channels (I<sub>Kr</sub>).<ref name="pmid14693686">{{Cite journal |vauthors=Clark RB, Mangoni ME, Lueger A, Couette B, Nargeot J, Giles WR |date=May 2004 |title=A rapidly activating delayed rectifier K+ current regulates pacemaker activity in adult mouse sinoatrial node cells |journal=American Journal of Physiology. Heart and Circulatory Physiology |volume=286 |issue=5 |pages=H1757–66 |doi=10.1152/ajpheart.00753.2003 |pmid=14693686}}</ref>