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Cardiac Action Potential
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0:08
Hello, I m Eric Strong from Strong Medicine, and this is the second video in this series on the cardiovascular system. The topic is the cardiac action potential. By the end of the video, you ll be able to list the general characteristics of ion channels, define the equilibrium potential, describe the ionic basis for the resting membrane potential, and list the phases of the fast and slow response action potentials, as well as the
0:35
ions and currents responsible for each phase. Cardiac ion channels and the action potentials they help generate is a frustratingly complex topic, with a greater number of individual channels and currents then I can realistically include in a video like this. I ll just be focusing on those which have a reasonable degree of clinical relevance in understanding classic genetic diseases, mechanisms of arrhythmias, and the mechanisms
1:03
of action of antiarrhythmics. Fortunately, these are also the channels and currents discussed in medical school courses. But be aware that this video will not be telling the complete story.
1:20
To understand the action potential, we first need to understand the resting membrane potential. But before that, we need to understand some very basic concepts related to ion channels.
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Ion channels are proteins that span the cell membrane that are selectively permeable, meaning they can discriminate ions based on their size and charge. And they can either open or close in response to different types of stimuli a property known as gating.
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When open, ion channels allow the passive diffusion of ions from one side of the membrane to the other. What determines the direction of ions flow? Well, for one thing, ions want to move down their chemical gradient moving from an area of high concentration to low concentration. But they also want to move down the electrical gradient as determined by the ion s charge and the electrical potential difference or the voltage
2:15
across the membrane. Sometimes, these two gradients are in the same direction.
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However, if these gradients are in opposing directions, there will be net movement of ions only until the forces caused by two gradients balance one another. That is, if the ion channels are open, there will be net movement of an ion until its net electrochemical gradient is zero. The transmembrane voltage required to perfectly balance the diffusion force from a concentration gradient is known as the equilibrium potential which I ll talk more about in a minute.
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Aside from the electrochemical gradient, the passage of an ion through its respective channels is also dependent on whether the channels are physically open. Most ion channels can be either open or closed, regulated by the presence of a part of the protein called a gate. If the gate is open, the channel is open and the ion can pass through.
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The gates that control whether a channel is open or closed come in two primary types:
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Ligand-gated channels, also known as chemical gated, open and close based on the binding of neurotransmitters, hormones, and second messengers. And voltage-gated channels open and close based on changes in the electrical potential across the membrane. An individual channel can even have more than one type of gate which respond to different stimuli, or which respond to the same stimuli but with different effect or with different kinetics meaning speed.
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For example, the cardiac voltage-gated sodium channel, formally known as NaV1.5 has two voltage gates one designated the activation gate or m gate, and the other the inactivation gate or h gate. When the membrane is depolarized, the activation gate opens relatively quickly, while the inactivation gate closes relatively slowly. The consequence of these two specific gates is that NaV1.5 has 3 states. Rather than just closed vs. open, it has closed
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vs. open vs. inactivated. Once inactivated, only repolarization returns the inactivated channel back to the closed state, at which point a subsequent depolarization can open it again.
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The membrane potential, which I ve already alluded to, is the electrical voltage across the cell membrane, which is predominantly the result of an imbalance between the flow of ions. Let s see where that imbalance comes from. Cardiomyocytes, like all cells in the body, contain a protein called the sodium-potassium ATPase or sodium-potassium pump. This is an enzyme that spans the cell membrane and which facilitates the active transport of sodium and potassium.
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Specifically, it uses the energy derived from 1 molecule of ATP, to transport 3 sodium ions out of the cell, in exchange for moving 2 potassium ions into the cell. The pump is doing this all the time, to varying degrees, in every cell in our body and this one action is responsible for a significant fraction of our body s overall energy expenditure. As more sodium and potassium ions are exchanged, there are 3 obvious direct consequences.
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First, the concentration of sodium in the extracellular space increases.
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Second, the concentration of potassium in the intracellular space increases.
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And third, the cell becomes negatively charged relative to the outside environment. In absolute terms, the new imbalance of charge is small, but is still significant enough to generate an electrical potential across the cell membrane, which is usually shortened to membrane potential, abbreviated V sub m. By convention, membrane potentials are designated intracellular relative to extracellular. So if the membrane potential is one which would tend to pull positive charge
6:15
into the cell, it s a negative membrane potential. I ve labeled it -3mV here, but don t worry too much about the actual value which will vary a bit between different cell types. The main point is that the sodium-potassium pump establishes concentration gradients, and has a relatively small direct contribution to making a negative membrane potential.
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For a cell at rest meaning a cell not currently experiencing an action potential the cell membrane is relatively impermeable to sodium ions, meaning it has low conductance to sodium, abbreviated g sub Na, because the vast majority of sodium channels are closed. So despite the high concentration of extracellular sodium, sodium cannot leak through the cell membrane down its electrochemical gradient. However, the membrane is mildly permeable to
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potassium ions via open channels, such that some amount of potassium leaks out of the cell, driven down its concentration gradient. As potassium ions diffuse out of the cell in this way, the ions move against their electrical gradient, further increasing the electrical potential across the membrane. This added amount to the transmembrane potential is called the diffusion potential, because it s generated by the diffusion of an ion down its concentration gradient. At some point,
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an equilibrium is reached in which the chemical gradient driving potassium out of the cell is balanced with the electrical gradient pulling potassium into the cell. The membrane potential at which this equilibrium is reached for potassium is called the potassium equilibrium potential. In other words, the equilibrium potential of an ion is the membrane voltage that perfectly balances that ion s tendency to diffuse down its concentration gradient.
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It s the potential at which the ion is at its electrochemical equilibrium. It should be noted that only a quantitatively small number of potassium ions need to move across the cell membrane to have a significant impact on the electrical potential, such that the intracellular concentration of potassium is not significantly decreased by this process. The equilibrium potential for potassium can be calculated from the Nernst equation.
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Some of these values are constants, we can assume a temperature of 37 degrees Celsius, and convert from the natural logarithm to common logarithm to get a more familiar version of the equation.
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The equilibrium potential for potassium equals 61.5 times the log of the potassium concentration outside of the cell over the potassium concentration inside the cell. For normal values of extracellular potassium of 4 and intracellular potassium of 135, this works out to a equilibrium potential of -94 millivolts.
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The Nernst equation can be applied to any ion, not just potassium. For example, using it for sodium, we can calculate its equilibrium potential for normal intra and extracellular sodium concentrations to be +71 millivolts. You might wonder if potassium is only in electrochemical equilibrium when the transmembrane potential is -94, and sodium is only in electrochemical equilibrium when the transmembrane potential is +71, does that
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mean that both ions cannot be in equilibrium at the same time? And that s correct. Each ion has a tendency to pull the cell s overall membrane potential towards its own equilibrium potential in which the contribution of each equilibrium potential is related to the permeability, that is, the conductance of the membrane for that ion. The higher the conductance for an ion, the closer the membrane potential will be to that ion s equilibrium potential.
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Mathematically, this can be calculated using the chord conductance equation. If we plug in our previously calculated equilibrium potentials, and empiric measurements of membrane conductance, we find an overall resting membrane potential for a typical cardiomyocyte of -90 millivolts. This is nearly the same as that of the potassium equilibrium potential because the cell membrane is far more permeable to potassium than sodium. Other ions such as calcium, phosphate, and negatively
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charged proteins are present too, however, since the cardiomyocyte membrane at rest is largely impermeable to these, they play a negligible role in determining the resting membrane potential.
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Different cell types in different tissues and in different ionic environments will have slightly different resting membrane potentials, but they are always negative.
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In summary, the resting membrane potential is the stable electrical potential across the cell membrane caused by ions, predominantly potassium, flowing down the electrochemical gradient that was established by the sodium-potassium pump. The specific value of the resting membrane potential is determined by the relative conductances of ions, and their relative concentrations inside vs. outside the cell. Maintenance of the resting membrane potential
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requires the continuous expenditure of energy in the form of ATP.
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I m finally at the action potential, but before descending into the details of what channel opens when, I m going to spend a few minutes talking about it more generally. On the most basic level, the action potential is a mechanism by which excitable cells, such as neurons and myocytes, can rapidly transmit electrical signals along their cell membranes and to adjacent cells. The action potential consists of a transient, stereotypical change in membrane
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potential that s caused by a sequence of ion channels opening and closing. The details of the stereotypical change in an individual cell, that is, the shape that the action potential takes, differs depending on the properties of the ion channels which are expressed within that cell.
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Ion channels vary between cell types and between tissues. I ll obviously be focusing on those within the heart, where the purpose of the action potential is to trigger myocyte contraction and ejection of blood out of the heart. First, the typical cardiac action potential looks something like this, where this is a graph of membrane potential as a function of time. The action potential starts as an initial decrease in the magnitude of the negative resting membrane
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potential, meaning it gets closer to zero. This is known as depolarization because it s associated with the cell becoming less polarized. If whatever stimulus is causing depolarization stops early, the membrane potential returns to the resting membrane potential. But once a specific threshold potential is reached, the triggering of a full, complete action potential is inevitable. This is known as an all-or-none phenomenon. Either the action potential happens or it doesn
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t. Once the action potential is triggered by the membrane potential having reached the threshold, full depolarization of the cell occurs due to an inward flow of positively charged ions. After cell has been depolarized followed by a slight dip, there is a plateau during which the membrane potential is relatively constant near zero due to the inward and outward flow of ions roughly balancing one another. And then there is a sudden shift favoring the outward flow of
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positively charged ions causing the cell to rapidly repolarize back to the resting membrane potential. Not every action potential looks precisely like this. For example, there are differences between ventricular action potentials
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immediately adjacent to the epicardium which have a notch immediately after depolarization, and those immediately adjacent to the endocardium which do not. There are also differences in the shape between action potentials in the atria vs. the ventricles, in which atrial action potentials tend to have a less pronounced plateau phase than in the examples I ve shown. But the general shape throughout the myocardium is roughly similar with a notable exception of the so-called
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slow response action potential in pacemaker cells, which I ll talk about in a few minutes.
14:33
Returning to this version of the shape, I ll next discuss the refractory period. Immediately after a region of the cell membrane has experienced an action potential, there exists a duration of time during which a repeat electrical stimulus will fail to trigger a subsequent normal action potential. The majority of the refractory period is the absolute refractory period, in which no subsequent action potential can occur.
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This is largely due to the inactivated state of the previously mentioned cardiac sodium channel. The channel cannot be reopened until repolarization returns it to the closed state in which the inactivation gate is opened, and for this to happen takes a finite amount time.
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A small portion of the refractory period is the relative refractory period, during which an action potential can be generated but with an abnormal shape and only after a larger than normal stimulus. In some but not all cardiomyocytes, the refractory period is followed by a very brief supranormal period during which the cell is *more* excitable than normal meaning it requires less of a electrical stimulus to trigger an action potential.
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Some references also make a distinction between the absolute refractory period and a very slightly longer effective refractory period which also contains a brief moment when an action potential can be generated but not propagated. To the best of my knowledge, the distinction between the absolute refractory period and the effective refractory period has no clinical significance, and many references treat these two terms as synonyms.
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Action potentials spread along cell membranes, in any and all directions at once, except through areas that are currently refractory. They are very effective when an electrical signal needs to rapidly propagate through adjacent myocytes such as in the heart, where this rapid spread through the myocardium allows the near simultaneous contraction of either the 2 atria or the 2 ventricles. Within the heart, the speed of propagation,
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also known as conduction velocity, varies in different locations. It is fastest in the Purkinje fibers so the signal can be distributed even more quickly across the myocardium.
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It is slowest in the AV node in order to accommodate additional ventricular filling during the atrial kick at the end of ventricular diastole.
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In neurons, the typical initial trigger for an action potential is a neurotransmitter that s released from the end of one axon and travels across a short gap between cells known as a synapse to bind to receptors on the receiving axon. In contrast, in cardiac myocytes, the normal initial trigger comes from special cells called pacemaker cells - found in places like the SA node - that spontaneously depolarize
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under the control of the autonomic nervous system and which communicate to adjacent myocytes via cell-to-cell connections called gap junctions. These gap junctions are relatively non-selective about which ions they allow to pass through and have low electrical resistance which allows current to easily pass from one cell to the next. The rate of depolarization experienced by pacemaker cells is influenced by hormones and neurotransmitters, though even in isolation
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from the nervous system, these pacemaker cells will still depolarize on their own.
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There are two basic types of actional potentials in the heart. The overwhelming majority of cardiomyocytes display the fast-response actional potential, which has the shape I ve been showing throughout the video. The fast-response action potential has 5 phases which I ve sort of already introduced without referring to them as such. The numbering of the phases is a little odd but it s a universal convention.
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We start at phase 4, which is when the cell is sitting at its resting membrane potential.
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Phase 0 is the rapid upstroke, or rapid depolarization. Phase 1 is a brief period of modest early repolarization. Phase 2 is the plateau the prominence of which is unique to action potentials within the heart, compared to those within neurons or skeletal muscle.
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Phase 3 is slightly less rapid, complete repolarization And then we re back to resting membrane potential and phase 4.
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There are different ion channels and currents that are responsible for each of these phases. I m going to go through the sequence of currents twice using 2 different figures, which is going to sound redundant, but it will help to understand what s going on, and to remember it.
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Some of the currents are depolarizing currents, which are caused by the inward movement of positive ions. And some currents are repolarizing, which are caused by the outward movement of positive ions.
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During phase 4, the cell is sitting at its resting membrane potential. Remember from a few minutes ago that the resting membrane potential is maintained by the slow, consistent outward movement of potassium ions. This current is called I sub K1, which is also known as the inwardly rectified potassium current. The term inward rectified is a little confusing, and for the most part, you don t need to worry about it. But, it refers to the fact the relevant
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channels conduct inwardly directed currents much more easily than outwardly directed ones.
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Phase 0 is caused by inward movement of sodium through the voltage-gated sodium channel previously introduced. When the membrane voltage is depolarized to the threshold potential by an adjacent action potential, the sodium channel s rapidly responsive activation gate opens, allowing an influx of sodium, which then rapidly further depolarizes the membrane. Even after the membrane voltage has crossed zero and is now positive, the large concentration
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gradient will still drive sodium into the cell, despite it being against its electrical gradient. This period during which the membrane potential is positive is occasionally referred to as the overshoot. This continues for a very brief period of time until the sodium channel s slowly responsive inactivation gate closes, abruptly stopping that inward current.
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Phase 1 is due to a current descriptively called a transient outward current, and designated I sub t o. It is predominantly caused by the outward movement of potassium ions, driven by both the concentration and electrical gradients.
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During phase 2, the fact that there is a plateau in the voltage waveform means there must be balancing currents. In this specific case, there is an inward calcium current which is mediated by one of two types of calcium channel called the L-type. L-type channels are also voltage-gated, and are relatively slowly inactivated, with the L standing for long-lasting. Beyond just the action potential, the influx of calcium is also important for the process of excitation-contraction
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coupling, to be discussed in a future video. The other type of calcium channel is the T-type, for transient, which does not play a major role in generating or propagating the action potential.
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The inward calcium current is balanced with an outward potassium current, mediated by two channel types collectively referred to as delayed rectifier potassium channels.
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Phase 3 begins once the L-type calcium channels have closed, and there is nothing to counterbalance the delayed rectifying potassium current. This unopposed outward current leads to complete repolarization back to the resting membrane potential, and the cell is back to phase 4 again. Something you may have noticed regarding the I sub K 1 current, or the inward rectifying potassium current - it basically shuts off
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throughout the action potential until the second half of phase 3 when it restarts and is the current most responsible for the final portion of repolarization.
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So I m going to go through that again, but summarized only hitting the highlights.
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Phase 4 is due to outward movement of potassium, known as the inwardly rectified current. Phase 0 is due to inward movement of sodium. Phase 1 is predominantly from outward movement of potassium.
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During phase 2, there is a balance between an inward movement of calcium through L-type calcium channels, and an outward movement of potassium known as the delayed rectified current. And by phase 3, the calcium channels have closed, and outward movement of potassium is unopposed, including a restart of the inwardly rectified current just before return to the resting membrane potential.
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The second type of action potential is the slow-response, and luckily, it s a bit simpler. In this case, instead of 5 phases, there are just 3. Unlike in cells that use the fast-response action potential, in cells that use the slow-response one, there is not a stable resting membrane potential. Instead, in between action potentials, the membrane slowly but spontaneously depolarizes. When the spontaneous gradual depolarization
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reaches the threshold potential, phase 0 starts with a depolarization that s somewhat fast, but not nearly as much so as depolarization in the rapid-response actional potential.
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After the depolarization, there is no plateau so no phase 1 or phase 2, but rather just phase 3 that consists of a more gradual repolarization. When it reaches a minimum membrane potential, we re back to phase 4 again and the slow spontaneous depolarization.
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Notably, the minimum membrane voltage in cells that exhibit spontaneous depolarization is significantly less negative than the resting membrane potential of about -90 mV characteristic of most cardiomyocytes. What s the ionic basis for this action potential? Phase 4 is caused by an inward sodium current, that is literally named, the funny current, abbreviated I sub f. Some prefer to call this current the pacemaker current, but even when
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they do, it s still abbreviated I sub f. Phase 0 is due an inward calcium current. And phase 3 is due to an outward potassium current.
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So where in the heart would the slow-response action potential be most important? Well, where in the heart is it necessary for cells to spontaneously depolarize? Pacemaker cells, like for example in the SA node. The process by which pacemaker cells in the SA node spontaneously depolarize is known as automaticity. As the SA node is the normal site for initiating cardiac electrical activity, the frequency of automaticity there sets the overall heart rate. Factors that
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determine the automaticity most obviously include the slope of phase 4 depolarization. The steeper the slope, the faster the threshold potential will be reached, and the faster the heart rate. Other less important factors include the nadir of the membrane potential after an action potential has fired, as well as the overall duration of the action potential.
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The slow-response action potential isn t limited to only the SA node. There are also cells within the AV node, bundle of His, and Purkinje fibers, known as latent pacemakers, which also have the ability to exhibit automaticity, but do so at slower rates than the SA node. As a consequence, a latent pacemaker will usually only take over control of the heart rate if all latent pacemakers with faster intrinsic rates have failed.
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Let s summarize what I ve discussed. Ion channels are transmembrane proteins with display selective permeability of ions based on charge and size, and which have gates that are controlled either by ligands or by changes in voltage.
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Ion channels allow movement of ions across the cell membrane, down their electrochemical gradients.
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The sodium potassium pump establishes concentration gradients across the cell membrane, resulting in a relatively high extracellular sodium concentration and a relatively higher intracellular potassium concentration. It creates a small membrane potential on its own. And because creating these gradients and membrane potential is work, it requires energy in the form of ATP.
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The equilibrium potential of an ion is the transmembrane voltage, also known as membrane potential, that perfectly balances an ion s tendency to diffuse down its concentration gradient. It can be calculated from the Nernst equation. The resting membrane potential is the actual voltage that exists across a cell membrane in between action potentials. It can be calculated as a weighted average of ions equilibrium potentials,
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based on the membrane s conductance to each ion. The greater the conductance for an ion, the more of an influence that ion s equilibrium potential has on the overall resting membrane potential. In cardiomyocytes, the resting membrane potential is determined predominantly by the equilibrium potential for potassium, because when at rest, the membrane is relatively impermeable to other ions.
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And last are the phases of the 2 types of action potential and the relevant currents.
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In the fast-response action potential, phase 4 is the cell sitting at its resting membrane potential so is dependent primarily on outward potassium current. Phase 0 is rapid depolarization due to inward sodium current. Phase 1 is the modest early repolarization phase, primarily due to outward potassium current. Phase 2 is the voltage plateau, when inward calcium current balances outward potassium current. And phase 3 is repolarization due to unopposed outward potassium current.
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In the slow-response action potential which is expressed within the SA node and latent pacemakers, phase 4 consists of slow depolarization due to inward sodium current usually called the funny current. Then the slow depolarization hits the threshold potential, phase 0 is triggered due to inward calcium current. And phase 3 is repolarization due to outward potassium current.
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That concludes this video on the cardiac action potential. As always, if you found the video helpful, please consider sharing it with classmates and colleagues, and consider subscribing to Strong Medicine for the rest of this ongoing series on the cardiovascular system, as well as a large collection of video on other medical topics.
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