NBL Module 7 Video Lecture 2

>> We're going to begin, in this lecture, to talk about a type of gated ion channel, which is called a voltage gated channel. And this type of channel is an ion channel that is selective for specific ion, and it opens in response to a depolarization of the membrane potential. It turns out that the three types of voltage gated channels are voltage gated sodium, voltage gated potassium, and voltage gated calcium channels. And in this lecture, we'll be talking about the voltage gated sodium and potassium channels. It turns out that the rising phase of the action potential involves the activation of voltage gated sodium channels. These channels are normally closed at the resting membrane potential and when the membrane potential becomes more positive than threshold, which is -55 millivolts, then these channels open. Once these channels are open, there is a very dramatic increase in the sodium influx into the neuron and this is a sodium current. When those sodium ions flow into the neuron, they're going to bring their positive charge with them, and this will produce a depolarization of the membrane potential. So remember from our discussion of Ohm's Law, we have the current is equal to the voltage times the conductance, and the voltage is the driving force. And you remember that the driving force is equal to the membrane potential minus the Nernst potential. So going back to our calculations of the driving force, at the resting membrane potential, the driving force for sodium is very large. If we say the average resting membrane potential is about -67 millivolts and we know that the Nernst potential for sodium is 60 millivolts, this gives us a driving force for sodium at the resting membrane potential of -127 millivolts. Now, in order for there to be a current, there has to be a conductance, which is an open ion channel. So when the voltage gated sodium channels open, then they're going to allow the sodium to flow into the neuron and this will produce an inward current, and because it is negative here because of the driving force, we talk about this as being a negative current. Now, currents can be either negative or positive depending on the direction in which the ions are flowing and also the charge of the ion. So the inward movement of positive ions into the neuron will produce a negative current. So if we depolarize the membrane potential beyond threshold, that's going to lead to the opening of the voltage gated sodium channels, and this will produce an inward current. Now, what you can see is that this inward current is transient. And the reason for this is the voltage gated sodium channels, once they open, they close again. And this is referred to as inactivation. And we'll talk about the mechanism of this in a few slides. This shows the depolarization that is produced during the rising phase that depends on the activation of the voltage gated sodium channels. And here we can see the opening and the influx of sodium in individual channels if we sum all of the channels together, this gives us our inward sodium current. So I'd like to go back and just talk about this concept of threshold. And the idea is that there is a specific membrane potential at which these voltage gated sodium channels are activated. And this threshold is about -55 millivolts. So if we see here, if we were to step the membrane potential in a neuron using an electrode, we would see that there would be a response, we would get an influx, there would be a depolarization of the sodium, which would lead to this type of graded response here. But if we step the membrane potential beyond -55 millivolts, what you can see is that the membrane depolarizes and then it initiates the production of an action potential. And this action potential then is going to be a very specific stereotypical type of response, and interestingly, what you see is that if the membrane potential remains depolarized beyond -55 millivolts, then after about four or five milliseconds or so, this neuron will fire a subsequent action potential. And as long as the membrane is depolarized beyond -55 millivolts, it will continue to fire action potentials. So this threshold of -55 millivolts is exactly the membrane potential that is involved in the opening and activation of the voltage gated sodium channels. The important part of the neuron, where this threshold is critical, is at this region which is called the initial segment of the axon hillock. And the reason that this is the place where threshold is important is because this is the first place along the axon where the voltage gated sodium channels are localized. And so even though the membrane potential could be depolarized to -40 or -30 millivolts anywhere else in the neuron, the only place that the meaning of threshold is important is at the initial segment. Now, this is a typical type of interneuron, sensory neurons have got an axon, actually has two axon branches. And this region here, which is very close to where the receptors are for the sensory modality, this is the place that is comparable to the initial segment. So the initial segment, the sensitivity then depends on the voltage dependence of the ion channels and also the density of the ion channels that are localized here. And usually threshold is approximately -55 millivolts, but it can be more positive for that for different neurons depending on the specific types of voltage gated channels that they express, so it can be slightly more positive all the way up to about -40 millivolts, depending on the density of the ion channels and the specific voltage dependence of those ion channels. This is an immunofluorescence micrograph that shows a neuron in culture, and the voltage gated sodium channels are imaged in red here. And what you can see is this is a neuron, and it's got a cell body and lots of dendrites, and this is the axon hillock. And here, this is the expression of the voltage gated sodium channels. And you can see that the density is highest in this part of the axon. And again, this is another neuron in culture, and what you can see is that we're also imaging the voltage gated channels. And you have an axon here, which is projecting from the cell body. And in this particular dye, we're looking at voltage gated channels. And we can see that there are synapses all over this neuron, and so these would be the presynaptic regions where these synapses are present. So the initial segment, which is the trigger zone, is the first place along the axon where the voltage gated channels will be localized. >> So the voltage gated channels have an interesting property that they give rise to a positive feedback loop. So we have a depolarizing stimulus, and we have the depolarizing stimulus is going to cross threshold, so it will be more positive than -55 millivolts. This leads to the opening of the voltage gated sodium channels that are found in the initial segment. This is going to increase the current, it's going to increase the permeability to sodium, and that will allow for the production of the sodium current as the sodium ions flow into the neuron. Then the sodium ions, what they will do is that they'll depolarize the membrane potential, and that depolarization then provides a positive feedback towards the opening of more voltage gated sodium channels. Now the membrane potential then is going to control the activation or the open state of the voltage gated channels. And then once the membrane becomes depolarized, then it will produce the opening of additional voltage gated channels. The voltage gated channels have this interesting property in that once they have opened, they have a built in inactivation mechanism as well. So after about a millisecond or so, the channels that were originally opened will inactivate and they will close. And this means that because they're inactivated, even though the membrane potential is still beyond threshold, those channels are closed and they will not be able to open up again until the membrane potential has gone back to and returned to the resting membrane potential. So this is a cartoon that depicts the structure of a single voltage gated sodium channel. And this is a very, very large protein that you can see, has got 24 transmembrane spanning domains, and each one of these transmembrane domains is an alpha helix. But you can see that these individual groups of alpha helices are repeated along the structure. So we have this region, which is called DI which contains six trans membrane spanning domains. And there's also a small loop that inserts into half of the lipid by-layer. And then this type of structure, this sequence, is repeated four times throughout the entire channel. This shows what the entire protein would look like when it comes together, is inserted into the plasma membrane. You can see each one of these regions then is going to help to form the channel pore region. So these transmembrane spanning domains, each one of these repeats has got two specific functions. One of them is to act as a detector for the change in the membrane potential. This region here called S IV, so it is the fourth region that is present within this group. And this S IV region is the voltage sensor for the voltage gated channel. And you can see then, because this is repeated, that each one of these D II and III, IV regions each got an S IV voltage sensing domain. In addition, also these two regions here, S V and S VI are going to be involved in producing the ion channel pore region. So you can see here, they're going to be coming together with other regions. And then this is the region that will be involved in actually allowing the sodium ion to cross across the plasma membrane. So getting back to this voltage sensor, then you can see that there are these little plus signs here, and what this indicates is that the S IV domain contains a series of positive amino acids that are present within the membrane spanning domain. The other amino acids are hydrophobic like other transmembrane spanning domains, but you can see here there are a series of positive amino acids. It's these positive amino acids then that are going to allow for this voltage sensor region to move in response to changes in the membrane potential. Now this is the region of the channel. This is the channel part that produces the pour. It also turns out that there are additional channel sub units which allow for the binding of intracellular domains and allow for the tethering of these channels to specific regions. And when we talk about myelination and the nodes of Ron VA, this localization concept is going to become even clearer and its importance will be reflected. So here is the single voltage gated sodium channel, and we're only looking at one of the individual repeat domains. And so here we have the voltage sensor region, and what you can see are a series of positive amino acids that are all on one specific part of this voltage sensor domain. And what happens is that when the membrane potential is at its resting membrane potential, so we have it be more negative here you can see that these positive charges, are all attracted to these negative charges of the membrane potential. But then as the membrane potential becomes more positive, when threshold is met, it becomes more positive than -55 millivolts. What that's going to do is it will repel these positive amino acids that are in the voltage sensor El. And this electrical force then is going to produce a movement of the S IV domain. And so we talk about this a movement within a protein as being a conformational change. And as soon as the membrane potential is -55 or so, then it's going to kick that whole region of the S IV part of the protein, it's going to move it. When it does that, that movement will be then transduced to other regions within the channel, and that will lead to the opening of the voltage gated channel. So this region here, when it moves, it's going to produce the movement of the S V, 6 regions, which are the parts of the channel which are involved in forming the poor and allowing the sodium ions to move. So when we talk about the activation of the voltage gated channel, that means we're talking about the movement of these transmembrane domains, which will allow for the formation and the opening of the poor region, which will then allow the sodium ions to move down their electro-chemical gradient. >> So as I mentioned, in addition to this Alpha sub unit here, there are also these accessory or auxiliary sub units, including the Beta sub units, which are depicted here. And these Beta sub units are not really involved in forming the channel per se, but they're involved in localizing the sodium channel protein to specific regions within the axon. Now this is particularly important for myelinated axons in which the voltage gated sodium channels are localized to a specific region, which is called the nodes of Ranvier. And so you can see here that these voltage gated channels then are going to be linked to, they bind to, intracellular proteins, scaffolding proteins, and cytoskeletal proteins, and help to localize the voltage gated channels to the specific regions. These are not indirectly involved in forming the pore, but these auxiliary subunits can also modulate things like the sensitivity of the channel to voltage and the open time. So they can affect the properties of the voltage gated sodium channel. So here's another cartoon that depicts the opening and activation of the voltage gated channel and also demonstrates this property that it has for inactivation. So at the resting membrane potential, the region which we call the gate here, which is going to be the part that will allow the sodium ions to move through the pore region, at the resting membrane potential, given the conformation of the voltage sensor region and the S5 and S6 region, these channels are closed. So at the resting membrane potential, the voltage gated sodium channels are in a closed state. Then when the membrane potential becomes depolarized, that's going to induce the movement of the S4 region. And when the S4 region moves, then the S5 and S6 regions will move and that will allow for the opening of the gate. So the gate region will move here and that will allow the sodium ions to move down their electrochemical gradient. And this will produce the sodium current that will then depolarize the membrane potential even more and lead to that very large depolarization that's mediated during the rising phase of the action potential. Now, once the channel is open though, the channel has got this protein domain here on the cytoplasmic side, which is called the channel inactivating segment. And once the channel pore region is open, this channel inactivating segment swings over and binds to the cytoplasmic region of the pore and that's going to close it and prevent it from being able to allow sodium ions to move across the membrane. And so this is a built in inactivation mechanism that depends first on the activation, so you have to have this initial conformational change so now that the channel inactivating segment can bind to the mouth of the pore and block it. And as I mentioned, once this occurs, this is a state, this is what we call the closed and inactivated state. And even though the membrane potential is still depolarized here, this channel is not able to contribute, it's not able to open again until the membrane potential goes back to the resting membrane potential. So it requires repolarization of the membrane, closure of the gate, and then displacement of this channel inactivating segment to get the channel back to a closed but activatable state. So this tells us then, that the voltage gated channels exist in three separate states; the closed active state, the activated open state, and the closed inactive state. Now this property of this voltage gated sodium channel is actually very critical for a number of aspects of the conduction of the action potential. It is going to determine the directionality of the conduction of the action potential and will also determine how rapidly a subsequent action potential would be able to be fired. And we'll talk about this when we talk about the refractory periods during the action potential. So if we look at the time course of this, we see that the initial opening occurs very rapidly, within an order of about a tenth of a millisecond. And then this inactivation takes about a millisecond or so to occur. So these are very rapid types of kinetics. And so these voltage gated channels are only open for a tiny fraction of a second before they inactivate but because the driving force for sodium is so great, we have a very large sodium current that will be able to flow when these channels initially are opened before the channel inactivates. So this just shows the region of the axon here. So this would be the initial segment of the axon hillock. And this is the first place along the axon where our voltage gated sodium channels are localized. If the membrane potential becomes more positive, so it crosses threshold, it goes from minus 67 at resting membrane potential to about minus 55 millivolts and that's because of all the summed activity that is incoming activity from all the synaptic activity that would be present and would just be passively propagating along the membrane. So if there is more excitatory synaptic transmission or less inhibitory synaptic transmission, then you would have the depolarization of the membrane, which would be passively moving along the membrane which would then be sensed by these voltage gated sodium channels that are localized at the initial segment. As soon as the membrane becomes more positive, becomes depolarized beyond threshold, so minus 55 millivolts, then, the summed graded potential would then allow for the activation of the voltage gated sodium channels and then sodium will flow down its electrochemical gradient and there's a very large driving force at the resting membrane potential. The sodium is going to flow into the cytoplasm of the axon, which we call the axoplasm and that will depolarize the membrane potential. But remember, those sodium ions are going to be able to move, they're going to move along the membrane, and they can also move into the cytoplasm. As they move along the membrane, the sodium ions will depolarize the adjacent regions of the axonal plasma membrane. And if there are voltage gated sodium channels that are nearby, then those channels, once the sodium has depolarized the membrane potential, that sodium current then will allow for the depolarization and the adjacent voltage gated channels will be activated. This open property is transient though. So as soon as the channels have been opened, they will become inactivated. And so these channels will eventually close, but the nearby channels will be activated by the sodium current induced depolarization. And so now this region of the axonal membrane will become depolarized. And we'll talk in the next lecture about conduction of the action potential. And this is exactly the mechanism whereby the movement of the action potential will occur along the axon. And the axon contains voltage gated sodium channel all along its length and so the action potential will be able to conduct from this region at the initial segment, all the way down to the presynaptic region. >> So we have these three states of the channel, then we have the closed but activatable state. We have the open activated state, and we have the closed inactive state. And this just depicts the currents that are being produced by the opening of the voltage gated channel. So you can see that there is this inward sodium current, but after these sodium channels have opened, they're going to immediately inactivate and so you can see that this current will decrease all the way back to zero because of the inactivation property. So even in the continued presence of depolarization of the membrane, then this sodium current will be transient. And as I mentioned, this inactivation is important because it allows for the membrane to repolarize back to the resting membrane potential. And it helps this other activity, which is the opening of the voltage potassium channels. It helps to contribute to the repolarization of the membrane potential by that particular mechanism as well. So an interesting compound has been discovered that is an inhibitor of voltage gated sodium channels and this is a naturally occurring molecule which is called tetrodotoxin. And tetrodotoxin is a toxin that is produced by puffer fish. And it is thought that this is a toxin that evolved to be a protective mechanism that allows puffer fish to protect themselves from their predators and this is the molecular structure of tetrodotoxin. And what tetrodotoxin does is that it is a blocker of the voltage gated sodium channels. So normally we see there's this inward sodium current when we depolarize the membrane potential. But if we pretreat the membrane or the cell with tetrodotoxin, then that leads to an inhibition of this voltage gated sodium current. Now it turns out that there are many other different types of animal toxins which have the same type of function and that they are inhibitors or blockers of the voltage gated sodium channels. Now, this tetrodotoxin is used mainly in the laboratory in order to block voltage gated sodium channels when electrophysiologists want to investigate other types of channels and currents that are present within cells. Another type of inhibitor of the voltage gated sodium channels are what we call the local anesthetics. And these include lidocaine and novocaine and here are the structures of lidocaine and novocaine. So these are called local anesthetics because they are injected locally to inhibit the voltage gated sodium channels. And one of the places that they're used is in the prevention of pain in dental procedures and they're also used as topical local anesthetics. So we talked about the sensory neuron so this is a cartoon of a somatosensory neuron. It's got its sensory endings here. And these neurons will produce action potentials and it's actually got two branches of an axon so there's an axon that comes from where the stimulus is being generated and it sweeps right by the cell body and then the action potential will go into the spinal cord. These axons will innervate neurons that are present in the spinal cord. And as inhibitors of the voltage gated sodium channels, these drugs will block the production of action potentials, as well as the conduction of action potentials, because the conduction also requires voltage gated sodium channels. And so these can be used as local anesthetics because they actually block the detection of information for the detection of painful stimuli that are present either within the skin or in the muscles or the joints. So I talked about the fast positive cycle of the voltage gated sodium channels. So we have the opening of the channels, increased permeability to sodium, the sodium current which depolarizes the membrane and this allows for a positive feedback because it's the depolarization that will open additional voltage gated sodium channels. But this voltage gated sodium channel activity is followed by the activation of another type of voltage gated channel, and these are the voltage gated potassium channels. Voltage gated potassium channels are also opened by depolarization of the membrane potential and they have a very similar threshold of about -55 Mv for their activation and their opening. When these channels open though, they take a lot longer in order to activate and for this opening process than the voltage gated sodium channels. So they are much slower in their opening and so this increased conductance to potassium takes longer and there will be an increased flow of potassium out of the cell in response to the opening of these voltage gated potassium channels. But it occurs more slowly after the voltage gated sodium channels are opened. Now, the reason that potassium will flow out of the cell is because the driving force for potassium is such that it has an electro chemical gradient where these ions are going, there's a higher concentration of potassium on the inside and the resting membrane potential is negative, but not as great as the nernst potential for potassium. But still these potassium ions will flow out. And what that is going to do, is it's going to repolarize the membrane potential? And what that means is it will bring the membrane potential from a more positive value back to a more negative value, and it will repolarize the membrane potential back to the resting membrane potential. Now, this loop is actually a negative feedback loop because the purpose of the outflow of potassium to repolarize the membrane potential is actually going to bring it back to a more negative value, which will prevent the opening of additional voltage gated potassium channels. So its function then, is to repolarize the membrane potential. But as it's doing that, then the additional voltage gated potassium channels will not have the necessary threshold in order to open, and so this will provide a negative feedback loop. So here we have our voltage gated sodium channels, and this will lead to the depolarization of the membrane potential as the sodium ions are moving inside the cell. This will lead to a depolarization of the membrane potential. As the membrane becomes more depolarized, that will activate nearby voltage gated sodium channels. And then in about a millisecond or so later, you have the activation of the voltage gated potassium channels and what that will do is allow potassium to flow down its electrochemical gradient out of the cell. And that as we remove the positive charges, that's going to repolarize the membrane potential back to a more negative value, back to the resting membrane potential, which will lead to the repolarization phase of the action potential. And at this stage, the voltage gated sodium channels have become inactivated, so they're not going to contribute anymore to the depolarization of the membrane potential so these two are never fighting each other in terms of controlling the membrane potential. >> These voltage gated potassium channels are quite similar to the voltage gated sodium channels, except there's one major difference. There's actually two major differences. It turns out that the individual sub-units. So we have these six transmembrane spanning domains, are in these six regions are in a separate proteins. The voltage gated potassium channels are made up of four separate sub-units, with each of these sub-units containing these six transmembrane spanning domains. The Regions 5 and 6 are involved in the pore forming region. They allow for the channel part of the protein so that where the potassium ions can flow through. Then it's also got this S4 region which is the voltage sensor S4 domain. It works in a mechanism that's very similar to the voltage gated sodium channels when the membrane potential becomes more positive, this S4 region moves, and then this conformational change is transmitted to S5 and S6 so the channel can be open. In the one way that it's different is that there are four separate sub-units that come together. And then a second way it's different is that the voltage gated potassium channels do not have an inactivation gate region. These channels do not inactivate like the voltage gated sodium channels do. This channels are one of the major categories of voltage gated potassium channels are referred to as delayed rectifier potassium channels. And are called this because they're delayed, they open more slowly than the voltage gated sodium channels. And they're called rectifiers because they're going to bring the membrane potential back from a positive value all the way to the resting membrane potential. If we want to look at the current that is flowing, what we see is that the current is equal to the driving force times the conductance. The driving force is the membrane potential minus the equilibrium or Nernst potential for potassium. If we consider the peak of the action potential at the peak of the action potential is about positive 30 millivolts. At that value then, the driving force for potassium would be 30 millivolts minus negative 84 millivolts, which would be positive 124 millivolts. Because it's positive, this means that the potassium ions are going to be flowing out of the cell and you can see that a couple of things here first, the activation of the voltage gated potassium channels is slower, so it's delayed compared to the activation of the voltage gated sodium channels. And also, this current remains present even when the membrane potential is held at a depolarized level. So this is not a transient channel because these channels do not inactivate. This is a cartoon showing that we have these four separate gene products, four proteins here, and each one has the six membrane spanning domains with each one has got the S4 domain. Here this just shows how the S4 domain could potentially move in response to the depolarization of the membrane potential and how that would be transduced into the opening of the channel. The great majority of voltage gated potassium channels do not inactivate, but what they do is to repolarize the membrane potential back to the resting membrane potential. And at the resting membrane potential, that's the potential which is going to lead to the closing of the voltage gated potassium channels. Also the voltage gated channels, they activate more slowly than the voltage gated sodium channels. This is what we call a dendrogram, and this is for ion channels that allow positive ions to move through them. This is also referred to as a phylogenetic tree. Over here we have the most ancient ion channels, which are shown here at the very center of this dendrogram and then this just shows the evolution of different types of ion channel as a function of time during evolution. What we have here, these are some of the oldest channels, so these are thought to be the precursors in evolution. These are the leak potassium channels here. During evolution we have the evolution of the voltage gated potassium channels. It's thought that the potassium channels are the oldest phylogenetically, in terms of their evolution. Then here we have a branch which gives rise to the voltage gated sodium channels, and they are related to the voltage gated calcium channels as well. Now, here's another category of potassium channels, a different type, which are called the inward rectifier channels. Then we have these channels over here, which are called the TRP channels. These channels, they're not selective. They allow both sodium and potassium to flow through them. These channels are really important because these are the channels that are involved in sensory transduction. These are the channels that are activated by changes in temperature or changes in pressure. And these are the ones which will initially depolarize the membrane potential to produce an action potential in the sensory neurons. We have talked now about the depolarization, which is mediated by the activation of the sodium voltage gated channels, and then the repolarization, which is dependent on the activation of the voltage gated potassium channels. Interestingly, even though the membrane potential has reached the resting membrane potential, and the majority of the voltage gated potassium channels will now be closed. It turns out that there's an additional undershoot phase. The membrane potential repolarizes and then actually hyperpolarizes beyond the resting membrane potential. This is because of the activation of a number of additional potassium channels. There are a few voltage gated channels which remain open, which can be modulated and then there are other potassium channels like the SK potassium channels and the calcium activated potassium channels. These are different potassium channel families and they are activated at this phase of the action potential. You can see as potassium channels they have a very similar overall structure with these six transmembrane spanning domains. But then they have additional protein regions which can be modified, for example, by calcium and other activities. This channels are important because they will affect the time course of the falling phase and the time course of the after hyperpolarization period of the action potential. What you can see here is an example of some different types of action potentials in different neurons or in muscle cells. You can see that even though the rising phase has a very similar type of time course, it's very rapid. This falling phase can be either extremely rapid or it can be much slower. And this rate of repolarization and the extent of this undershoot are determined by the voltage gated potassium channels, though the concentration and the sensitivity and the activity of these voltage gated channels, as well as the expression of these additional potassium channels, which will affect the length of period of the undershoot. This time course for the repolarization is actually quite important because it will help to determine how quickly after an initial action potential is generated. It's going to determine how rapidly a subsequent action potential will be produced. >> So we have these specific time periods during the action potential which we call the refractory period. And there are two types of refractory periods. There's a type which we call the absolute refractory period and the other one is the relative refractory period. During this time, which is about a millisecond after the initial depolarization beyond threshold to activate the voltage gated channels, it lasts for about a millisecond or so, and during this absolute refractory period, no matter how much depolarization of the membrane potential occurs, because these voltage gated channels are inactivated and they can't open, it is not possible for the neuron to generate another action potential during this period. And the absolute refractory period is important because it ensures that the action potential will be propagated in only one direction, and that is from the cell body toward the axon presynaptic region. And it also determines what we call the theoretical maximal frequency or rate of action potentials. And that means because the voltage gated sodium channels are inactivated and closed during this period and they can't be opened again until the membrane potential gets back to the resting membrane potential, then that means that another subsequent action potential could not be produced until this period about right here. And so if it takes one millisecond for an action potential to be produced, then the maximum frequency of action potential production is one action potential per millisecond. And if we express that in hertz, that is 1,000 hertz. Now, the other type of refractory period is the relative refractory period. And this is the time from about one millisecond back to when the resting membrane potential has gone back to its level. This relative refractory period is determined by the voltage gated potassium channels and the other potassium channels that are being activated during this period. And what this will do is, as the potassium channels are being activated, they will repolarize the membrane potential, and as they're repolarizing the membrane potential then, that means that that is going to affect how much total summed input activity will be required to produce a subsequent action potential. So these potassium channels then are going to determine the amount of time that it takes before the membrane potential will get back to the resting membrane potential and where the voltage gated sodium channels will be ready to be activated again. So what you can see here is that if you were to depolarize the membrane potential during this period here, it would be difficult to generate a subsequent action potential, but if you gave a larger stimulus during this period, then this neuron would be able to fire a subsequent action potential. And we'll talk about the basis of this refractory period. We'll talk about this a little bit more in our subsequent lecture. So to summarize then, we have the production of an action potential which is triggered by the level of the membrane potential being meeting threshold, and this, for most neurons, is about -55 or maybe slightly less -54 or 53 millivolts. When this happens, when threshold is met, this will lead to the activation of a few voltage gated sodium channels. The ones that are in a conformation where that S4 region is the most sensitive to the membrane potential. Once these voltage gated channels open then, that will lead to an influx of sodium, which will depolarize the membrane potential and now many more voltage gated sodium channels will open. And this is a sodium current. It's an inward current, and because you have the inward movement of positive ions, we consider this a negative. This is a negative current. This influx of sodium is going to depolarize the membrane potential all the way up to this region, which we call the peak of the action potential. And in a typical neuron, the peak is about positive 30 millivolts. So this demonstrates that this is a very large change in the membrane potential all the way from -67 millivolts, all the way up to positive 30 millivolts. So this is a change or a delta of close to 100 millivolts in terms of the response. So comparing that to the small EPSPs that we talked about in the synaptic responses, which are on the order of about 1-2 millivolts, this is a very, very large change in the membrane potential. Now, at about +30 millivolts, so this is really the time at about one millisecond or so after the activation of the voltage gated channels, these voltage gated sodium channels will inactivate and they will close. And so the sodium current will stop then, so there's a much less of a sodium current as the membrane potential becomes closer to the Nernst potential for sodium. And then also we don't have a conductance anymore because these voltage gated sodium channels are closed. Now, during this period here, we have the activation of the voltage gated potassium channels. They open more slowly, so it takes them between about a half a millisecond and a millisecond to open. And once they are open then, that's going to produce the potassium outward current. And at the peak of the action potential, you can see that there would be a very large driving force for potassium to move out of the cell because the membrane potential has become very positive and, so this produces a large potassium current. And it's an outward current because of the electrochemical gradient for potassium now. And potassium, as those ions move out of the cell, they're going to repolarize the membrane potential back to the resting membrane potential. When the membrane potential gets close to the resting membrane potential then, these voltage gated potassium channels are going to close, but there are additional potassium channels that will be opened during this period and, so even more potassium is going to flow out. And you can see that this level of membrane potential gets very close to the Nernst potential for potassium. So it gets all the way down to about -75 or so millivolts. Eventually, the signals that are opening keeping these additional potassium channels open, those signals will decrease and, so those additional potassium channels will be closed and the resting membrane potential will go back to its specific level. And of course, during this entire period, we've had the activity of all of the active transporters which are continuing to pump sodium and potassium ions against their concentration gradient. And then of course, that will help to contribute to the reestablishment of the resting membrane potential. Now, it's great that we have the production of a single action potential, but the important thing is that the action potential will be conducted, and it'll be conducted along the length of the axon from the cell body, all the way to the pre synaptic region. And that's what we'll talk about in the next lecture.