Editing Cardiac action potential (section)

===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>