Understanding Action Potentials and Ion Channels

That gets repeated close together over time. So if you looked at panel c over here, w w w, that is not the start of the website. That is the same signal that we're seeing repeated over and over and over again. And eventually those signals all stack together and we get an action potential because we've reached threshold. Temporal summation is different from spatial summation because spatial summation is going to involve different stimuli. And in this particular example, we had mentioned that stimulus y is actually giving us an example of hyperpolarizing that membrane. Remember, hyperpolarizing is when we become more negative. Generally, we associate that with inhibitory activities, whereas w is going to be an excitatory stimulus, and we said that depolarizes the membrane because it makes it less negative and brings it closer to threshold. K? So when those 2 stimuli, which are different, combine, we end up with a sum total of nothing. Right? And by the way, that sum total does not always look like this, a straight line. If we have 2 excitatory signals, that could bring us to threshold. If we have 2 different stimuli here that are inhibitory, that could really hyperpolarize. K? So the way in which those spatial signals or spatial stimuli can sum together looks different depending on what the stimuli are. My knee just cracked big time. Okay. So just as kind of a recap, I've already said this within the past 5 minutes, but to make sure we're on the same page, why are radiant potentials unable to communicate over long distances? Bella. It decays over time. It decays over time. Thank you. Very good. Right? They decay over time. They lose their strength. K? Only have enough of them. They can sum together and they can fire an action potential, which then can communicate over a long distance, but one individual radiant potential is not capable of doing that because it decays. Alright. Let's look a little bit closer at action potentials, and we're specifically going to be focusing on how ion movement causes an action potential to happen, and we'll spend some time really discerning between sodium channels and potassium channels. So when talking about an action potential in a neuron, sodium and potassium are going to be the 2 primary players. And that's great because you all are experts on coding of potassium at this point. So as a reminder, when we're talking about changes to the membrane potential, we can consider resting membrane potential, which is typically our reference point. We can consider depolarizing events, repolarizing events, and hyperpolarizing events. And so to put that all in a graphical depiction, on the left here, we've got our membrane potential that's on the y axis. We've got an x axis that doesn't exist, and that's okay because we're just looking at changes in that membrane potential. So this dotted line here at minus 70, that is indicative of our resting potential in our neuron. So, again, this is kind of our reference point and any deviation away from that reference point is going to fall into one of these 3 categories. It's either depolarizing, depolarizing, or hyperpolarizing. If we depolarize away from our reference point or that resting potential, that means that our membrane potential is getting more positive. K. So we see this green arrow that's pointing up. That's because we are becoming less different. Right? Remember polar means different or opposite. And so as that membrane potential becomes more positive, we're seeing a less of a difference of charge across that membrane. If we are talking about repolarizing, we are returning from a depolarization event, and we are coming back down to our reference point, which again is our resting potential. And then the alternative here is to instead of depolarizing and then repolarizing, we can instead hyperpolarize. And hyperpolarize is when we go beneath minus 70 or beneath our resting potential and become really, really negative. Okay? So we're not just different across the membrane. We're really different across the membrane. So these three activities, depolarizing, repolarizing, and hyperpolarizing, those are gonna be words that we use consistently as we speak about action potentials. Because we're using that language so much, I wanna make sure we all understand what that means. Does anyone have any questions about depolarizing, repolarizing, or hyperpolarizing? Great. Okay. So those are the ways within which our membrane potential can change. If we have a change in membrane potential, it's because we have a change in the distribution of charge. And if we have a change in the distribution of charge, that means charged particles or ions are moving across that membrane. And as you all know, ions can't just diffuse simply across the membrane. Because they are charged, they cannot interact with that hydrophobic core of the membrane, which means that we need to be considering ion channels as we're talking about events associated with depolarizing, repolarizing, and hyperpolarizing. Right? There has to be ion channels involved. Very generally speaking, there are 3 different types of ion channels. Weak channels, we've already spoken about. We mentioned these when we were talking about establishing a resting membrane potential, and a leak channel is something that's always open. They're located throughout the the length of the neuron, and they're important as we've already stated for maintaining resting membrane potential. And if you remember back to our earlier conversation about establishing that resting potential, we had said that as it pertains to leak channels, there's way more potassium leak channels than sodium leak leak channels. Okay? The other kind of ion channel that we have is a ligand heated channel, and this is a really funny one to me. So I'm not from Minnesota. I'm from Pittsburgh, and throughout my entire academic training, I learned this word as ligand, and it wasn't until I came here to St. Scholastica and I heard doctor Eder, who's now over in the title 9 office, pronounce that word, and she says ligand. So I don't know how anyone in this room says it, but evidently, both are correct, but I cannot I cannot say ligand. It just does not work for me. I will always say ligand. So I just wanna bring that to your attention if that sounds funny to you. I don't actually know what the correct pronunciation is. I just know how I was taught it, so so that's how I'm gonna speak about it. So a ligand gated channel is the second type of ion channel, and these will open or close in response to a ligand binding to it. Basically, a ligand is a part of a molecule that can attach to something else. So you can just think of it as like this extra part of a molecule that attaches to something. Okay? The ligand indicated channels are found in 2 distinct parts of the neuron. They're found in the dendrites of the neuron, and they're also found in the cell body. And then the third type of ion channel is the voltage gated channel. Voltage gated channels, as the name implies, they open or close in response to a change in memory potential, I e, and a change in voltage. K? So you can think about a change in a memory potential as being synonymous with a change in voltage. Okay? Sodium and potassium voltage aided channels are located throughout the neuron, but they're really concentrated in the axon, and particularly this is true in the axon hillock. Action potentials are very much a product of changes in these voltage gated channels, so we're gonna be talking about voltage gated channels a lot today and next week. The other kind of voltage gated channel that's gonna be really important to our conversation around action potentials is the calcium voltage gated channel. And the calcium voltage gated channel is found in the axon terminal, and it plays a really important role in the release of a neurotransmitter. And we'll talk about what that looks like next week, but keep in mind that the calcium voltage data channel is only found at the terminal, the axon terminal, and it plays an important role in releasing those neurotransmitters. And thinking more about this sort of ion gating in axons, keep in mind that changes in membrane potential are gonna be controlled by changes in the flow of ions through those channels. Potassium has 2 kinds of channels that we're gonna be speaking about, potassium lead channels, which as we've mentioned are always open, and then these voltage gated potassium channels, which open when there's a particular membrane potential that is reached, but generally they're closed at resting potential. Okay? So a voltage gated channel, you should assume, is always going to be closed until permeable to sodium at rest, which you already knew that. Right? Membrane is far more permeable to potassium at rest. Sodium is really only going to be using voltage gated channels. Okay. So let's look at phases of an action potential. Let's figure out what this actually looks like and what's going on. Alright. So, again, we're looking at the basis of the action potential. Of course, if we're talking about an action potential, we need to draw ourselves a graph because that's the best way to understand what's going on. So on the y axis here, we're gonna have our membrane potentials. And as a reminder, that's going to be measured in millimoles. And kind of the the the potentials that we want to keep in mind for the sake of the action potential, minus 70. Right? Remember, that's our resting membrane potential. Minus 55. What is minus 55? Has to do with raising potentials? Yeah. Richie? The threshold. The threshold. Right. Very good. The threshold. Right? So when you have upgraded potentials and you reach threshold, then we are absolutely firing an action potential. We've admitted there's no falling back. And then the other number to keep in mind, it's gonna be way up here. This is positive 30 millivolts. Positive 30 millivolts is the peak membrane potential during an action potential. So what does an action potential look like rapidly? You've seen this already, but to draw it out, we're kind of bumping along here at rest. We have some graded potentials. We start to slowly depolarize, and then we hit threshold and bam happens. K? So what's going on here with these different phases? So the first phase of our action potential is this section right here. Right? This is phase 1. And what's happening during phase 1 is depolarization. The next phase, phase 2, starts at the end of phase 1. It comes all the way down to minus 70. That's phase 2. Phase 2 is repolarization. And then this last phase is phase 27. I'm just kidding. This is phase 3. Just wanna make sure we're all paying attention. This is phase 3. K. Phase 3, what activity is going on in phase 3? How would you how would you classify that? We depolarized. We've repolarized. What are we doing here? Hyperpolarized. Very good. Okay. So this is our action potential. Right? We've got phase 1, phase 2, phase 3 where we have these discrete activities going on here. This region right here where we're initially depolarizing, where we're having graded potentials, this is not part of the action potential. Right? Because at this point, as you've already seen, we could potentially not reach threshold. We could potentially repolarize and just come back to rest. So this is not considered to be part of the action potential. The action potential does not start until we hit minus 55. That's like a really, really important line in the sand. If we take a closer look at our voltage gated sodium channels, these are channels that only open up once the membrane has reached threshold. Right? So at minus 65 millivolts, that is the exact moment when our voltage gated sodium channels open up. And when that happens, because sodium has such a strong positive equilibrium potential, it's so different from the resting potential. As soon as those gates open up, sodium floods in. It goes into that cell as fast as it can at a really strong magnitude. So it rushes into that cell due to the electrochemical gradient. The membrane potential very rapid rapidly climbs towards the equilibrium potential for sodium, and then these channels will turn off or deactivate at 30 millivolts. K? So that really rapid spike that we see in phase 1 of the action potential, that happens because sodium floods into the cell so fast, and because sodium is positively charged, that very, very, very rapid influx of positive charge causes that very, very, very rapid spike. There are 2 different gates that control the sodium channel, and this is important and this is historically where things get a little bit confusing, so make sure you're paying attention. There are 2 different gates here. There is an activation gate and then there is an inactivation gate. K? So looking at the structure of the sodium channel here, this is our sodium channel, our voltage gated sodium channel. This is our voltage gated sodium channel at rest. Okay? So if we're at minus 7 millivolts here, you'll notice that the channel is closed right in the middle here. Right? There's, like, a little pinch that happens. That little pinch is the activation gate, and then this little sort of ball and chain down here, this little structure, this is the inactivation gate. Okay? K? So 2 different kinds of structures here that both contribute to either the open state or closed state of that voltage gated sodium channel. There's the activation gate, which is the little pinched area right in between the channel, and then the inactivation gate, which is this little structure that hangs down here in the intracellular fluid. Both of these are going to be voltage dependent, so the activation gate is what opens up that threshold and the depolarization, and this happens in a positive feedback mechanism. So as soon as that membrane potential reaches minus 55 kilovolts, this little gate right here is going to open up, and so it will look like this. Sodium floods in, and once this membrane potential starts to get more and more positive, that will cause more and more and more of these activation gates to open up. Okay? So that's what I mean by a positive feedback mechanism. Once one opens, a whole bunch of them start to open because it gets more and more positive. And that will go on and on and on until we reach positive 30 millivolts. So once we reach positive 30 millivolts, that's when the depolarization phase of the action potential, phase 1, ends, and phase 2, which is that repolarization phase begins. Yeah, Joshua. So is is it repolarization or depolarization? For This isn't for both on them. Just one thing. For Down here. Yeah. So let's come back to this. So the activation gate will open up during depolarization, and then during repolarization, so right here, the activate the inactivation gate will plug up this channel, but the activation gate stays open. So this is where things get a little bit weird and confusing. So let's make sure we're all paying attention. Okay? So a positive 30 millivolts, this activation gate will pinch shut. Okay? Excuse me. Positive 30 millivolts, this activation gate stays open, and maybe that's where I'm in this book. K? So this activation gate will stay open and then a positive 30 millivolts, the inactivation gate will plug up the bottom of that channel. So this activation gate is still open, but now we're plugged up on the intracellular membrane side of that voltage gated sodium channel. I apologize if I misspoke there. K? So let's back up a little bit one more time to make sure we're on the same page. So we hit threshold. We're at minus 55. K? We move from this resting state to this state right here. K? The activation gate opens up, sodium floods into the cell, we climb our membrane potential really, really quickly. And then once we reach positive 30 millivolts, nothing happens to the activation gate, but instead, the inactivation gate, which was previously just hanging out down inside of the cell, the inactivation gate, the 30 millivolts will plug up the bottom of that voltage gated channel. So sodium can no longer come into the cell. So the mechanism that controls the opening is different here than it is here. Did you have a question? So this does stay closed during depolarization. Or excuse me. No. You're right. Damn. Okay. There's a mistake on the slide. Joshua, Damien. What is your name? Morgan Dean. Okay. Holy cow. Oh my gosh. Sometimes it takes a village. Okay. Good grief. Okay. Let's all just stop for a second, take a breath, and I'll come back. K. There was a mistake on the slide. This should read closes during repolarization, which is what I was saying, but the text did not read that. I apologize. This has been a week that has been rife with mistakes on my end. Good grief. I really do apologize, and thank you all for holding me accountable. Right? And the scary part about that is I've been using the slide deck for a long time, and no one has said that, which makes me a little bit concerned. And I've just kept again, so you know what? I'm just gonna keep open. I'm trying to get contacts and you all don't care about the contacts. It doesn't matter. Okay. So this is what's going on here. We've got an inactivation gate that is this little plug that hangs out in the intracellular fluid, and that inactivation gate is open during depolarization, but it closes or plugs up that channel during depolarization. K? So once we've reached 30 millivolts, this plugs up the channel and sodium cannot come in. K? This little plug, the inactivation gate behaves differently than the activation gate. Activation gate is inside and that closes at rest. That's what keeps sodium out at rest. The inactivation gain is what keeps sodium out during the second phase or that repolarization phase. K? Let's take a break from sodium. That was a little bit stressful. Let's talk about this potassium voltage beta channel. So potassium also has a voltage beta channel that opens up in response to a very specific membrane potential. The potassium voltage data channel is going to change its state around 30 millivolts, and 30 millivolts, if you remember, that is when we transition into phase 2 of our action potential, our repolarization phase. K? As a result of reaching 30 millivolts, these voltage gated potassium channels open up. Potassium rushes out of the cell. Right? Remember, potassium's electrochemical driving force is to move out. Potassium floods out of the cell, and that loss of positive charge is what repolarizes the membrane potential. Okay. So 2 things are happening at 30 millivolts. We've closed our sodium channels by plugging up the inactivation gate so sodium can no longer cross the membrane, while we've also opened our potassium channels and potassium floods out. So we are both we're no longer taking on a positive charge and we are actively losing a positive charge through potassium movement. And so collectively, both of those activities function to repolarize that cell membrane and bring us back down to a negative membrane potential. Potassium voltage gated channels are much more straightforward because there's only 1 and there's only 1 gate, so you don't have to worry about 2 different gates with the voltage gated potassium channel. It's going to depend on voltage and time, and this function through a negative feedback loop. So if we look at these membrane potential changes that happen during the action potential, we know that excitable membranes have the ability to generate action potentials, and we know that this action potential is a rapid large depolarization that we use for communication. And we use it for communication because this happens so quickly and so dramatically. Right? Going from minus 70 to positive 30 in a millisecond is a very, very, very radical shift. Okay? So that's really important for communication, particularly across long distances. And so if we look at neurons specifically, axons travel or excuse me, action potentials travel along the axon from the soma or the cell body to the axon terminal, and keeping in mind that some of your neurons are exceptionally long and this happens very, very quickly. And we'll talk about mechanisms that your body has in place to ensure that happens quickly, probably sometime next week, but just keep in mind that this is a really rapid action and it happens along the length of the axon until it reaches the axon terminal. Okay. So let's revisit these phases of the action potential through the lens of ion movement. Okay. So we're gonna talk again about ion movement and phases of our action potential. And having this discussion, we're going to clearly speak about these different gates. K? The different ion gates in our voltage gated channels and how those contribute to this entire process. So we've got just as a reminder for our different phases. Right. We've got our action potential that looks like this. Oops. Oh, too far there. We're repolarizing here, and then we are hyperpolarizing here. So let's look at our ion channels and ion permeability during each of these phases. K. So during phase 1. So during this phase, we've got a high permeability to sodium, and that is because our voltage gated channels for sodium are open, and that opening involves 2 gates. K? So both the activation and inactivation gates are open. Also during this time, this first phase of the action potential, there is a very low permeability to potassium. And that is because our voltage gated channels for potassium are closed. Alright. So that's the state of all of our channels, our voltage gated channels, and our ion permeability during phase 1. During phase 2, as we are repolarizing, we now have very low permeability to sodium. And that is because our voltage gated channels for sodium are closed. And specifically, they are closed at the inactivation page. And as a reminder, during this time, while the inactivation is closed, it's plugging up that channel, the activation gate is still open. Also during this time, contributing to that rapid repolarization is the notion that we have an increased permeability to potassium. And that is because our voltage gated channels for potassium are open. And then lastly, during phase 3, as we are hyperpolarizing, we're getting really, really, really negative. We see yet more changes in the faces of our gaze. So we have a very brief increased permeability to potassium. Yes, ma'am. Is that better? Okay. And that brief permeability to potassium is due to the fact that we enter this hyperpolarization phase with our voltage beta potassium channels open, but during this process, within this phase, those voltage beta potassium channels close. So during this time, voltage beta channels for potassium are actively closing. Right? So we get really, really negative. We approach the equilibrium potential for potassium, which remember is minus 94. And as we start to get really negative and really close to that membrane or that equilibrium potential, those voltage gated potassium channels start to close. Also during this time, we have a decreased permeability or a low permeability to sodium. What's different now and we're gonna have to come over here. I'm running out of space. What's different now, closed but where they are closed is different. So we are now closed at the activation gate, and then we're open at the inactivation gate. K. So during this phase of hyperpolarization or phase 3, we see that the mechanism plugging up that multituded sodium channel switches. So we pinch the inactivation gate shut, and once that's complete, the inactivation gate unplugs itself and hangs out back in the intracellular fluid again. And it will stay like this through resting membrane potential, through rated potentials until we start phase 1 again once we've hit threshold. Yeah. Yeah. Good question. So the question was, is there ever a point at which both of those gates are closed at the same time? For all intents and purposes, no. Right? For all intents and purposes, those 2 flip flop, There may be, like, a very, very brief, like, fraction of a fraction of a millisecond where they're closed at the same time, but all things considered, it's 1 or the other. Yeah. Good question. Can I take a picture of that? Yeah. Sorry. Oh, you're good. Okay. I'm trying to, like, I can't Is this compared to everyone, particularly after my snafu on that slide? Yes. Do we feel good about this? Okay. Excellent. Make sure my markers are closed. So we've got about 10 minutes left just under that. So having said all that, now that we understand how ions move and what the state of those channels looks like at different times, we can make kind of broad sweeping statements about how that permeability to sodium potassium changes throughout the duration of the action potential. And so let's take a look at this graph over here to the right. K? This is kind of a funny graph because we've got 2 y axes. K? We've got a y axis over here that's denoting membrane potential. This is what we've been looking at so far. Then we've got this second y axis over here, and look, this is looking specifically at membrane permeability. So we've got 3 different graphs here. Right? Three different lines. And 2 of these lines coordinate with this right y axis. One of these lines, the red line for the action potential, that coordinates with this left y axis. So I wanna make sure we're all clear on that. We've got 2 y axis here. Okay? And then on the bottom, we've got time as we usually do. So as we look at the different phases of the action potential, so we're depolarizing here during our graded potential, we reach threshold, we fire an action potential, we depolarize. During that depolarization phase, we see that our permeability for sodium climbs up just as the action potential continues to climb up. And the reason why it does this, why it isn't just immediately permeable, it's not a straight line, it's it's technically a slope that's slightly graded. The reason it's like that is because, remember, those voltage gated sodium channels function in a positive feedback mechanism, so they don't all open at the same time. Right? One opens and then others open and then they continue to start to open, and it happens in a very fast fashion, but it's not all at once. And that is indicative of that positive feedback mechanism of those voltage gated sodium channels. So we see permeability to sodium climbs just as the action potentials, membrane potential climbs, and then once we hit positive 30 millivolts and those voltage gated channels for sodium start to close, they plug up the inactivation gate, our permeability to sodium drops. That decrease in permeability to sodium is going to drop the action potential, membrane potential there. Right? So we start to become less positive and then we start to become negative and more negative. And then as this all happens, those voltage gated potassium channels start to open up. And so as those voltage gated potassium channels start to open up, we continue to, climb towards resting potential. We even start to hyperpolarize as potassium brings us closer to its equilibrium potential, and then as we sort of reestablish ourselves and come closer to resting potential, everything will close and our membrane permeability to sodium and potassium will go back to where it was at rest. So basically, we have these very permeabilities to these ions as we go through the action potential. During phase 1, highly permeable to sodium. During phase 2, we lose our permeability to sodium and we increase our permeability to potassium. Okay? And you'll note too that by the end of this, we've completely decreased our permeability to sodium. There's no permeability to sodium here at all. There's still a little bit of permeability to potassium. Why is that? Yeah. The membrane potential of potassium is closer to the rest and the membrane potential. So the membrane the equilibrium potential for potassium is closer to the resting potential of the cell. Yes. But if we're back towards the equilibrium potential, why are we still permeable to potassium here? More channels. More channels. Right. Remember those leak channels for potassium that are all over the cell, all over the neuron, and they're open all the time. So even when those potassium voltage channels close, we still have potassium crossing the membrane, and that's because we've got a lot of potassium leak channels. K. A lot of potassium leak channels, and so that keeps the membrane relatively close to potassium's equilibrium potential. Right? Okay. Just as a reminder, right, as we are reaching minus 55, this entire process is not due to a change in sodium permeability. This is due to a change in graded potentials. So keeping in mind that as we depolarize and approach threshold, that's entirely due to the impact of those graded potentials as they cross the axon, cell body and then they reach the axon hillock. Different things or activities that can trigger reaching threshold is going to be the rapid opening of sodium channels coupled with the slow closing of those sodium channels, slow opening of potassium channels, and just generally speaking, the opening of potassium channels and the closing of sodium channels is the reason why the action potential does not actually reach the equilibrium potential for sodium. So we're headed towards the equilibrium potential for sodium, which, remember, is positive 6 towards the equilibrium potential for sodium, which, remember, is positive 60, but we never actually reach it, and that is because at positive 30, we close those voltage gated sodium channels and we start to open those voltage gated potassium channels. Okay? So we never reach the equilibrium potential for sodium, and we don't even get that close to it. If you think about how close we get to the equilibrium potential for potassium as we hyperpolarize, right, we get pretty darn close to minus 94. Comparatively, we do not get that close to positive 60. Yeah. Yeah. So this membrane permeability correlates with these two blue lines. The dark blue line is permeability to sodium, that's what that p means, and this light blue line is representative of permeability to potassium. These two blue lines correlate with this y axis over here that looks at a change in membrane permeability. And then over here on the left axis, this is the membrane potential, which is measured by a voltage meter, And that voltage meter is indicating changes associated with this red line, which is the action potential. Does that make sense? Okay. It's just about 8:50. We've had a wild ride this morning. So let's all take a deep breath. Go enjoy our weekend. We'll come back and celebrate Harry Potter Week on Monday. Please do look for that email from me once her weekly quiz is available. Otherwise, have a great weekend, and

And in this particular example, we had mentioned that stimulus y is actually giving us an example of hyperpolarizing that membrane. Remember, hyperpolarizing is when we become more negative. Generally, we associate that with inhibitory activities, whereas w is going to be an excitatory stimulus, and we said that depolarizes the membrane because it makes it less negative and brings it closer to threshold. K? So when those 2 stimuli, which are different, combine, we end up with a sum total of nothing.

Right? And by the way, that sum total does not always look like this, a straight line. If we have 2 excitatory signals, that could bring us to threshold. If we have 2 different stimuli here that are inhibitory, that could really hyperpolarize. K?

So the way in which those spatial signals or spatial stimuli can sum together looks different depending on what the stimuli are. My knee just cracked big time. Okay. So just as kind of a recap, I've already said this within the past 5 minutes, but to make sure we're on the same page, why are radiant potentials unable to communicate over long distances? Bella.

It decays over time. It decays over time. Thank you. Very good. Right?

They decay over time. They lose their strength. K? Only have enough of them. They can sum together and they can fire an action potential, which then can communicate over a long distance, but one individual radiant potential is not capable of doing that because it decays.

Alright. Let's look a little bit closer at action potentials, and we're specifically going to be focusing on how ion movement causes an action potential to happen, and we'll spend some time really discerning between sodium channels and potassium channels. So when talking about an action potential in a neuron, sodium and potassium are going to be the 2 primary players. And that's great because you all are experts on coding of potassium at this point. So as a reminder, when we're talking about changes to the membrane potential, we can consider resting membrane potential, which is typically our reference point.

We can consider depolarizing events, repolarizing events, and hyperpolarizing events. And so to put that all in a graphical depiction, on the left here, we've got our membrane potential that's on the y axis. We've got an x axis that doesn't exist, and that's okay because we're just looking at changes in that membrane potential. So this dotted line here at minus 70, that is indicative of our resting potential in our neuron. So, again, this is kind of our reference point and any deviation away from that reference point is going to fall into one of these 3 categories.

It's either depolarizing, depolarizing, or hyperpolarizing. If we depolarize away from our reference point or that resting potential, that means that our membrane potential is getting more positive. K. So we see this green arrow that's pointing up. That's because we are becoming less different.

Right? Remember polar means different or opposite. And so as that membrane potential becomes more positive, we're seeing a less of a difference of charge across that membrane. If we are talking about repolarizing, we are returning from a depolarization event, and we are coming back down to our reference point, which again is our resting potential. And then the alternative here is to instead of depolarizing and then repolarizing, we can instead hyperpolarize.

And hyperpolarize is when we go beneath minus 70 or beneath our resting potential and become really, really negative. Okay? So we're not just different across the membrane. We're really different across the membrane. So these three activities, depolarizing, repolarizing, and hyperpolarizing, those are gonna be words that we use consistently as we speak about action potentials.

Because we're using that language so much, I wanna make sure we all understand what that means. Does anyone have any questions about depolarizing, repolarizing, or hyperpolarizing? Great. Okay. So those are the ways within which our membrane potential can change.

If we have a change in membrane potential, it's because we have a change in the distribution of charge. And if we have a change in the distribution of charge, that means charged particles or ions are moving across that membrane. And as you all know, ions can't just diffuse simply across the membrane. Because they are charged, they cannot interact with that hydrophobic core of the membrane, which means that we need to be considering ion channels as we're talking about events associated with depolarizing, repolarizing, and hyperpolarizing. Right?

There has to be ion channels involved. Very generally speaking, there are 3 different types of ion channels. Weak channels, we've already spoken about. We mentioned these when we were talking about establishing a resting membrane potential, and a leak channel is something that's always open. They're located throughout the the length of the neuron, and they're important as we've already stated for maintaining resting membrane potential.

And if you remember back to our earlier conversation about establishing that resting potential, we had said that as it pertains to leak channels, there's way more potassium leak channels than sodium leak leak channels. Okay? The other kind of ion channel that we have is a ligand heated channel, and this is a really funny one to me. So I'm not from Minnesota. I'm from Pittsburgh, and throughout my entire academic training, I learned this word as ligand, and it wasn't until I came here to St.

Scholastica and I heard doctor Eder, who's now over in the title 9 office, pronounce that word, and she says ligand. So I don't know how anyone in this room says it, but evidently, both are correct, but I cannot I cannot say ligand. It just does not work for me. I will always say ligand. So I just wanna bring that to your attention if that sounds funny to you.

I don't actually know what the correct pronunciation is. I just know how I was taught it, so so that's how I'm gonna speak about it. So a ligand gated channel is the second type of ion channel, and these will open or close in response to a ligand binding to it. Basically, a ligand is a part of a molecule that can attach to something else. So you can just think of it as like this extra part of a molecule that attaches to something.

Okay? The ligand indicated channels are found in 2 distinct parts of the neuron. They're found in the dendrites of the neuron, and they're also found in the cell body. And then the third type of ion channel is the voltage gated channel. Voltage gated channels, as the name implies, they open or close in response to a change in memory potential, I e, and a change in voltage.

K? So you can think about a change in a memory potential as being synonymous with a change in voltage. Okay? Sodium and potassium voltage aided channels are located throughout the neuron, but they're really concentrated in the axon, and particularly this is true in the axon hillock. Action potentials are very much a product of changes in these voltage gated channels, so we're gonna be talking about voltage gated channels a lot today and next week.

The other kind of voltage gated channel that's gonna be really important to our conversation around action potentials is the calcium voltage gated channel. And the calcium voltage gated channel is found in the axon terminal, and it plays a really important role in the release of a neurotransmitter. And we'll talk about what that looks like next week, but keep in mind that the calcium voltage data channel is only found at the terminal, the axon terminal, and it plays an important role in releasing those neurotransmitters. And thinking more about this sort of ion gating in axons, keep in mind that changes in membrane potential are gonna be controlled by changes in the flow of ions through those channels. Potassium has 2 kinds of channels that we're gonna be speaking about, potassium lead channels, which as we've mentioned are always open, and then these voltage gated potassium channels, which open when there's a particular membrane potential that is reached, but generally they're closed at resting potential.

Okay? So a voltage gated channel, you should assume, is always going to be closed until permeable to sodium at rest, which you already knew that. Right? Membrane is far more permeable to potassium at rest. Sodium is really only going to be using voltage gated channels.

Okay. So let's look at phases of an action potential. Let's figure out what this actually looks like and what's going on. Alright. So, again, we're looking at the basis of the action potential.

Of course, if we're talking about an action potential, we need to draw ourselves a graph because that's the best way to understand what's going on. So on the y axis here, we're gonna have our membrane potentials. And as a reminder, that's going to be measured in millimoles. And kind of the the the potentials that we want to keep in mind for the sake of the action potential, minus 70. Right?

Remember, that's our resting membrane potential. Minus 55. What is minus 55? Has to do with raising potentials? Yeah.

Richie? The threshold. The threshold. Right. Very good.

The threshold. Right? So when you have upgraded potentials and you reach threshold, then we are absolutely firing an action potential. We've admitted there's no falling back. And then the other number to keep in mind, it's gonna be way up here.

This is positive 30 millivolts. Positive 30 millivolts is the peak membrane potential during an action potential. So what does an action potential look like rapidly? You've seen this already, but to draw it out, we're kind of bumping along here at rest. We have some graded potentials.

We start to slowly depolarize, and then we hit threshold and bam happens. K? So what's going on here with these different phases? So the first phase of our action potential is this section right here. Right?

This is phase 1. And what's happening during phase 1 is depolarization. The next phase, phase 2, starts at the end of phase 1. It comes all the way down to minus 70. That's phase 2.

Phase 2 is repolarization. And then this last phase is phase 27. I'm just kidding. This is phase 3. Just wanna make sure we're all paying attention.

This is phase 3. K. Phase 3, what activity is going on in phase 3? How would you how would you classify that? We depolarized.

We've repolarized. What are we doing here? Hyperpolarized. Very good. Okay.

So this is our action potential. Right? We've got phase 1, phase 2, phase 3 where we have these discrete activities going on here. This region right here where we're initially depolarizing, where we're having graded potentials, this is not part of the action potential. Right?

Because at this point, as you've already seen, we could potentially not reach threshold. We could potentially repolarize and just come back to rest. So this is not considered to be part of the action potential. The action potential does not start until we hit minus 55. That's like a really, really important line in the sand.

If we take a closer look at our voltage gated sodium channels, these are channels that only open up once the membrane has reached threshold. Right? So at minus 65 millivolts, that is the exact moment when our voltage gated sodium channels open up. And when that happens, because sodium has such a strong positive equilibrium potential, it's so different from the resting potential. As soon as those gates open up, sodium floods in.

It goes into that cell as fast as it can at a really strong magnitude. So it rushes into that cell due to the electrochemical gradient. The membrane potential very rapid rapidly climbs towards the equilibrium potential for sodium, and then these channels will turn off or deactivate at 30 millivolts. K? So that really rapid spike that we see in phase 1 of the action potential, that happens because sodium floods into the cell so fast, and because sodium is positively charged, that very, very, very rapid influx of positive charge causes that very, very, very rapid spike.

There are 2 different gates that control the sodium channel, and this is important and this is historically where things get a little bit confusing, so make sure you're paying attention. There are 2 different gates here. There is an activation gate and then there is an inactivation gate. K? So looking at the structure of the sodium channel here, this is our sodium channel, our voltage gated sodium channel.

This is our voltage gated sodium channel at rest. Okay? So if we're at minus 7 millivolts here, you'll notice that the channel is closed right in the middle here. Right? There's, like, a little pinch that happens.

That little pinch is the activation gate, and then this little sort of ball and chain down here, this little structure, this is the inactivation gate. Okay? K? So 2 different kinds of structures here that both contribute to either the open state or closed state of that voltage gated sodium channel. There's the activation gate, which is the little pinched area right in between the channel, and then the inactivation gate, which is this little structure that hangs down here in the intracellular fluid.

Both of these are going to be voltage dependent, so the activation gate is what opens up that threshold and the depolarization, and this happens in a positive feedback mechanism. So as soon as that membrane potential reaches minus 55 kilovolts, this little gate right here is going to open up, and so it will look like this. Sodium floods in, and once this membrane potential starts to get more and more positive, that will cause more and more and more of these activation gates to open up. Okay? So that's what I mean by a positive feedback mechanism.

Once one opens, a whole bunch of them start to open because it gets more and more positive. And that will go on and on and on until we reach positive 30 millivolts. So once we reach positive 30 millivolts, that's when the depolarization phase of the action potential, phase 1, ends, and phase 2, which is that repolarization phase begins. Yeah, Joshua. So is is it repolarization or depolarization?

For This isn't for both on them. Just one thing. For Down here. Yeah. So let's come back to this.

So the activation gate will open up during depolarization, and then during repolarization, so right here, the activate the inactivation gate will plug up this channel, but the activation gate stays open. So this is where things get a little bit weird and confusing. So let's make sure we're all paying attention. Okay? So a positive 30 millivolts, this activation gate will pinch shut.

Okay? Excuse me. Positive 30 millivolts, this activation gate stays open, and maybe that's where I'm in this book. K? So this activation gate will stay open and then a positive 30 millivolts, the inactivation gate will plug up the bottom of that channel.

So this activation gate is still open, but now we're plugged up on the intracellular membrane side of that voltage gated sodium channel. I apologize if I misspoke there. K? So let's back up a little bit one more time to make sure we're on the same page. So we hit threshold.

We're at minus 55. K? We move from this resting state to this state right here. K? The activation gate opens up, sodium floods into the cell, we climb our membrane potential really, really quickly.

And then once we reach positive 30 millivolts, nothing happens to the activation gate, but instead, the inactivation gate, which was previously just hanging out down inside of the cell, the inactivation gate, the 30 millivolts will plug up the bottom of that voltage gated channel. So sodium can no longer come into the cell. So the mechanism that controls the opening is different here than it is here. Did you have a question? So this does stay closed during depolarization.

Or excuse me. No. You're right. Damn. Okay.

There's a mistake on the slide. Joshua, Damien. What is your name? Morgan Dean. Okay.

Holy cow. Oh my gosh. Sometimes it takes a village. Okay. Good grief.

Okay. Let's all just stop for a second, take a breath, and I'll come back. K. There was a mistake on the slide. This should read closes during repolarization, which is what I was saying, but the text did not read that.

I apologize. This has been a week that has been rife with mistakes on my end. Good grief. I really do apologize, and thank you all for holding me accountable. Right?

And the scary part about that is I've been using the slide deck for a long time, and no one has said that, which makes me a little bit concerned. And I've just kept again, so you know what? I'm just gonna keep open. I'm trying to get contacts and you all don't care about the contacts. It doesn't matter.

Okay. So this is what's going on here. We've got an inactivation gate that is this little plug that hangs out in the intracellular fluid, and that inactivation gate is open during depolarization, but it closes or plugs up that channel during depolarization. K? So once we've reached 30 millivolts, this plugs up the channel and sodium cannot come in.

K? This little plug, the inactivation gate behaves differently than the activation gate. Activation gate is inside and that closes at rest. That's what keeps sodium out at rest. The inactivation gain is what keeps sodium out during the second phase or that repolarization phase.

K? Let's take a break from sodium. That was a little bit stressful. Let's talk about this potassium voltage beta channel. So potassium also has a voltage beta channel that opens up in response to a very specific membrane potential.

The potassium voltage data channel is going to change its state around 30 millivolts, and 30 millivolts, if you remember, that is when we transition into phase 2 of our action potential, our repolarization phase. K? As a result of reaching 30 millivolts, these voltage gated potassium channels open up. Potassium rushes out of the cell. Right?

Remember, potassium's electrochemical driving force is to move out. Potassium floods out of the cell, and that loss of positive charge is what repolarizes the membrane potential. Okay. So 2 things are happening at 30 millivolts. We've closed our sodium channels by plugging up the inactivation gate so sodium can no longer cross the membrane, while we've also opened our potassium channels and potassium floods out.

So we are both we're no longer taking on a positive charge and we are actively losing a positive charge through potassium movement. And so collectively, both of those activities function to repolarize that cell membrane and bring us back down to a negative membrane potential. Potassium voltage gated channels are much more straightforward because there's only 1 and there's only 1 gate, so you don't have to worry about 2 different gates with the voltage gated potassium channel. It's going to depend on voltage and time, and this function through a negative feedback loop. So if we look at these membrane potential changes that happen during the action potential, we know that excitable membranes have the ability to generate action potentials, and we know that this action potential is a rapid large depolarization that we use for communication.

And we use it for communication because this happens so quickly and so dramatically. Right? Going from minus 70 to positive 30 in a millisecond is a very, very, very radical shift. Okay? So that's really important for communication, particularly across long distances.

And so if we look at neurons specifically, axons travel or excuse me, action potentials travel along the axon from the soma or the cell body to the axon terminal, and keeping in mind that some of your neurons are exceptionally long and this happens very, very quickly. And we'll talk about mechanisms that your body has in place to ensure that happens quickly, probably sometime next week, but just keep in mind that this is a really rapid action and it happens along the length of the axon until it reaches the axon terminal. Okay. So let's revisit these phases of the action potential through the lens of ion movement. Okay.

So we're gonna talk again about ion movement and phases of our action potential. And having this discussion, we're going to clearly speak about these different gates. K? The different ion gates in our voltage gated channels and how those contribute to this entire process. So we've got just as a reminder for our different phases.

Right. We've got our action potential that looks like this. Oops. Oh, too far there. We're repolarizing here, and then we are hyperpolarizing here.

So let's look at our ion channels and ion permeability during each of these phases. K. So during phase 1. So during this phase, we've got a high permeability to sodium, and that is because our voltage gated channels for sodium are open, and that opening involves 2 gates. K?

So both the activation and inactivation gates are open. Also during this time, this first phase of the action potential, there is a very low permeability to potassium. And that is because our voltage gated channels for potassium are closed. Alright. So that's the state of all of our channels, our voltage gated channels, and our ion permeability during phase 1.

During phase 2, as we are repolarizing, we now have very low permeability to sodium. And that is because our voltage gated channels for sodium are closed. And specifically, they are closed at the inactivation page. And as a reminder, during this time, while the inactivation is closed, it's plugging up that channel, the activation gate is still open. Also during this time, contributing to that rapid repolarization is the notion that we have an increased permeability to potassium.

And that is because our voltage gated channels for potassium are open. And then lastly, during phase 3, as we are hyperpolarizing, we're getting really, really, really negative. We see yet more changes in the faces of our gaze. So we have a very brief increased permeability to potassium. Yes, ma'am.

Is that better? Okay. And that brief permeability to potassium is due to the fact that we enter this hyperpolarization phase with our voltage beta potassium channels open, but during this process, within this phase, those voltage beta potassium channels close. So during this time, voltage beta channels for potassium are actively closing. Right?

So we get really, really negative. We approach the equilibrium potential for potassium, which remember is minus 94. And as we start to get really negative and really close to that membrane or that equilibrium potential, those voltage gated potassium channels start to close. Also during this time, we have a decreased permeability or a low permeability to sodium. What's different now and we're gonna have to come over here.

I'm running out of space. What's different now, closed but where they are closed is different. So we are now closed at the activation gate, and then we're open at the inactivation gate. K. So during this phase of hyperpolarization or phase 3, we see that the mechanism plugging up that multituded sodium channel switches.

So we pinch the inactivation gate shut, and once that's complete, the inactivation gate unplugs itself and hangs out back in the intracellular fluid again. And it will stay like this through resting membrane potential, through rated potentials until we start phase 1 again once we've hit threshold. Yeah. Yeah. Good question.

So the question was, is there ever a point at which both of those gates are closed at the same time? For all intents and purposes, no. Right? For all intents and purposes, those 2 flip flop, There may be, like, a very, very brief, like, fraction of a fraction of a millisecond where they're closed at the same time, but all things considered, it's 1 or the other. Yeah.

Good question. Can I take a picture of that? Yeah. Sorry. Oh, you're good.

Okay. I'm trying to, like, I can't Is this compared to everyone, particularly after my snafu on that slide? Yes. Do we feel good about this? Okay.

Excellent. Make sure my markers are closed. So we've got about 10 minutes left just under that. So having said all that, now that we understand how ions move and what the state of those channels looks like at different times, we can make kind of broad sweeping statements about how that permeability to sodium potassium changes throughout the duration of the action potential. And so let's take a look at this graph over here to the right.

K? This is kind of a funny graph because we've got 2 y axes. K? We've got a y axis over here that's denoting membrane potential. This is what we've been looking at so far.

Then we've got this second y axis over here, and look, this is looking specifically at membrane permeability. So we've got 3 different graphs here. Right? Three different lines. And 2 of these lines coordinate with this right y axis.

One of these lines, the red line for the action potential, that coordinates with this left y axis. So I wanna make sure we're all clear on that. We've got 2 y axis here. Okay? And then on the bottom, we've got time as we usually do.

So as we look at the different phases of the action potential, so we're depolarizing here during our graded potential, we reach threshold, we fire an action potential, we depolarize. During that depolarization phase, we see that our permeability for sodium climbs up just as the action potential continues to climb up. And the reason why it does this, why it isn't just immediately permeable, it's not a straight line, it's it's technically a slope that's slightly graded. The reason it's like that is because, remember, those voltage gated sodium channels function in a positive feedback mechanism, so they don't all open at the same time. Right?

One opens and then others open and then they continue to start to open, and it happens in a very fast fashion, but it's not all at once. And that is indicative of that positive feedback mechanism of those voltage gated sodium channels. So we see permeability to sodium climbs just as the action potentials, membrane potential climbs, and then once we hit positive 30 millivolts and those voltage gated channels for sodium start to close, they plug up the inactivation gate, our permeability to sodium drops. That decrease in permeability to sodium is going to drop the action potential, membrane potential there. Right?

So we start to become less positive and then we start to become negative and more negative. And then as this all happens, those voltage gated potassium channels start to open up. And so as those voltage gated potassium channels start to open up, we continue to, climb towards resting potential. We even start to hyperpolarize as potassium brings us closer to its equilibrium potential, and then as we sort of reestablish ourselves and come closer to resting potential, everything will close and our membrane permeability to sodium and potassium will go back to where it was at rest. So basically, we have these very permeabilities to these ions as we go through the action potential.

During phase 1, highly permeable to sodium. During phase 2, we lose our permeability to sodium and we increase our permeability to potassium. Okay? And you'll note too that by the end of this, we've completely decreased our permeability to sodium. There's no permeability to sodium here at all.

There's still a little bit of permeability to potassium. Why is that? Yeah. The membrane potential of potassium is closer to the rest and the membrane potential. So the membrane the equilibrium potential for potassium is closer to the resting potential of the cell.

Yes. But if we're back towards the equilibrium potential, why are we still permeable to potassium here? More channels. More channels. Right.

Remember those leak channels for potassium that are all over the cell, all over the neuron, and they're open all the time. So even when those potassium voltage channels close, we still have potassium crossing the membrane, and that's because we've got a lot of potassium leak channels. K. A lot of potassium leak channels, and so that keeps the membrane relatively close to potassium's equilibrium potential. Right?

Okay. Just as a reminder, right, as we are reaching minus 55, this entire process is not due to a change in sodium permeability. This is due to a change in graded potentials. So keeping in mind that as we depolarize and approach threshold, that's entirely due to the impact of those graded potentials as they cross the axon, cell body and then they reach the axon hillock. Different things or activities that can trigger reaching threshold is going to be the rapid opening of sodium channels coupled with the slow closing of those sodium channels, slow opening of potassium channels, and just generally speaking, the opening of potassium channels and the closing of sodium channels is the reason why the action potential does not actually reach the equilibrium potential for sodium.

So we're headed towards the equilibrium potential for sodium, which, remember, is positive 6 towards the equilibrium potential for sodium, which, remember, is positive 60, but we never actually reach it, and that is because at positive 30, we close those voltage gated sodium channels and we start to open those voltage gated potassium channels. Okay? So we never reach the equilibrium potential for sodium, and we don't even get that close to it. If you think about how close we get to the equilibrium potential for potassium as we hyperpolarize, right, we get pretty darn close to minus 94. Comparatively, we do not get that close to positive 60.

Yeah. Yeah. So this membrane permeability correlates with these two blue lines. The dark blue line is permeability to sodium, that's what that p means, and this light blue line is representative of permeability to potassium. These two blue lines correlate with this y axis over here that looks at a change in membrane permeability.

And then over here on the left axis, this is the membrane potential, which is measured by a voltage meter, And that voltage meter is indicating changes associated with this red line, which is the action potential. Does that make sense? Okay. It's just about 8:50. We've had a wild ride this morning.

So let's all take a deep breath. Go enjoy our weekend. We'll come back and celebrate Harry Potter Week on Monday. Please do look for that email from me once her weekly quiz is available. Otherwise, have a great weekend, and

Transcript for:Understanding Action Potentials and Ion Channels

Transcript for:
Understanding Action Potentials and Ion Channels