Neuro: 2:00 - 3:00Scribe: Matthew Davis

Wednesday, January 20, 2010Proof: Melissa Precise

Dr. LesterAction PotentialsPage1 of 6

  1. Introduction [S1]:
  2. This I where it gets a little more complicated because the membrane is not just sitting at rest. The reason that we need a membrane potential is that is the way to generate an electrical signal. We need to be able to alter that membrane potential and then that neuron can fire an action potential and get excited. That signal can propagate.
  3. There are a few things that come with action potentials that are confusing compared to other signals like synaptic signals so remember which one you are dealing with. When we talk about an action potential, they are called all or none. Once you have passed a threshold you get an action potential. If you don’t pass threshold you don’t get one. Synaptic signals are graded, there is no threshold so they can be small and grow in size.
  4. Action potentials self propagate or self regenerate so action potentials can generate themselves down the length of a membrane and it will be the same, you have the same distribution of ion channels, the same concentration of sodium and potassium. It will look the same when it started as where it ends.
  5. A synaptic signal will dissipate because it doesn’t regenerate. Where it is initiated at the synapse it will be the biggest and as it moves away it will get smaller and smaller and disappear. We will talk about the relationship of the cells resistance to why that happens.
  1. Ionic Basis of APs [S2]
  2. Why do we care? Action potentials are there to faithfully transmit information along the axon of excitable cells. Once this cell is integrated its synaptic information it either decides whether it generates, well the membrane decides because it is summing up all the excitatory and inhibitory inputs if it gets to this threshold it will fire an action potential. It might fire a burst of action potential and they will travel down the axon to the terminal where they do there thing perhaps synaptic transmission and transmit information to the next cell.
  3. We are concerned with how this is initiated and how it travels along the axon.
  1. Learning Objectives [S3]
  2. 2 or three channels are needed for the propagation of an action potential but there is not an agreed upon number
  1. 3 Phases of the Action Potential [S4]
  2. There are generally 3 major phases of the action potential. We talked already about the resting phase. WE have to have this negativity, this charge separation, because if we didn’t and there was no charge separation we wouldn’t be able to change the membrane potential because there would be no membrane potential. The whole point of resting membrane potential is to get the cell ready to fire an action potential.
  3. Depolarization which is the reversal of the membrane potential. By reversal I mean it is going to go from being negative inside to being positive inside
  4. Repolarization is a phase that brings it back towards resting membrane potential so it is ready to go again
  5. The action potential, once it goes, is on the order of a millisecond and in some cells it is longer or shorter but on the order of a millisecond is a good ballpark. Here we have a set up where we put an electrode in the cell to measure the transmembrane potential. Here its negative and positive outside at rest and we actually inject positive ions and we can reverse the membrane potential. You can see its reversed. Positive ions on the inside and negative on the outside.
  1. General Rule [S5]
  2. Go back to this diagram. If you know this you can understand everything that happens in the action potential. We sit at rest, so we put an electrode in the cell and it is sitting at -60mV and we start to open up a lot of sodium channels and what happens? Sodium is going to come in and it gets to a certain point where leaks, so as sodium comes in you increase the driving force on potassium because you have taken the membrane potential away from potassium and more potassium will leak out to try to overcome the incoming sodium. So threshold for getting an action potential happens when enough sodium comes in to overcome the leak of potassium. So then there is no way the potassium leaking out can keep up with sodium coming in and you get a full blown action potential. Around -50 to -55mV, a little above resting membrane potential, and then it will shoot up really fast and it will go toward the equilibrium potential for sodium but can’t go any further than that. When we open up channels for one ionic species the membrane potential will go towards its equilibrium potential and that is the absolute max it can go to.
  3. Now we know, because we measure it, that it won’t get all the way to the sodium equilibrium potential because it will get shut down before it reaches it. And when we measure it, it comes right back down and it goes down past the resting potential and eventually drifts back to rest. This is an important phase and we’ll come back to that.
  4. What would be a good guess for what ion is involved in repolarization? Potassium. Could it be anything else? It could be chloride, its not far off that. It could be either, when people first looked at this they didn’t know and they had to figure out which one by ion substitution rates. So it is potassium and it tends to come close down to the equilibrium for potassium because instead of just the few leak K channels we had open at rest we open up a ton more of K channels and close the sodium channels. The sodium channels inactivate and potassium channels open and we get it to rapidly come back down. Eventually the potassium channels close and only the leak ones are open and we are back at rest. You can see this kind of diagram helps you think. If you open up sodium channels you go up there and then I close them and open potassium and I come back down. Up here I have a huge driving force for sodium and not much for potassium. The cell uses driving potentials to change the membrane potential to wherever it wants
  5. If you get that then that is half of this lecture. You understand the ionic potential of the action potential. Sodium is responsible for upswing and potassium is largely responsible for the down swing.
  1. Depolarization [S6]
  2. In word form, the diagram I just went through. Rapid opening of sodium channels, sodium flows down its electrochemical gradient – big driving force that we have. The membrane potential is now much more permeable to sodium than potassium so the membrane potential moves towards the equilibrium of sodium. Because sodium is positive the action potential overshoots zero and the inside of the cell becomes positive. At the peak of the action potential sodium is the primary ion determining the membrane potential. We have a few leak potassium channels still open but we have a thousand more sodium channels open.
  3. Upswing is sodium
  1. Repolarization [S7]
  2. Now the downswing, there are two components. Clinically we know there are two components because if there is anything wrong with either one of them we get prolonged action potentials. Sodium channels inactivate because why try and repolarize using potassium channels if your sodium channels are still open because that will counteract the potassium. Sodium channels have done their job getting you depolarized. So we inactive the sodium channels and activate potassium channels to rapidly bring it back down. If either one of the ion channels aren’t working properly the action potential will be broader and more prolonged with a slower repolarization because of the counteracting ion channels.
  1. 2 Independent Channels [S8]
  2. So a little bit of pharmacology. Especially relevant to the local anesthetic lecture on Friday. Compounds that block sodium channels. I don’t want you to worry too much about this, instead of looking at voltage changes we are looking at current changes. TTX blocks the fast part of the response. This is the sodium part of the response. Sodium coming into the cell is represented here and TTX cleanly blocks it. You have to do this experiment this way and I don’t want to go into precise details but if you block the sodium part of the action potential with TTX you won’t get anything so you can’t study the other part that is left because you never get the sodium channels to open so that is why this experiment is done like this. So TTX blocks the sodium early part of the action potential but other compounds can block the later slower parts of the action potentials which is delayed and slower.
  1. Voltage-Gated Ion Channels [S9]
  2. This is a nice little diagram that discusses what goes on tin the action potential. We have sodium channels at rest, they are closed.They get activated by something, something needs to change to activate them and then they inactivate after a period of time, once they have depolarized for a millisecond then they inactivate. Then potassium channels open up in a similar manner to sodium ions. The gates open and potassium leaves the cell. One difference indicated is that sodium channels open first and faster and potassium channels open up later and slower. You don’t want your potassium channels to open too fast because the action potential would never get up to your sodium equilibrium potential, the potassium channels would counteract that. So sodium opens first, inactive sodium and then potassium activate later and repolarize
  3. The reason these channels get open is changes in membrane potential. Something ahs to trigger the opening of the sodium and potassium channels. They are opened by a change in voltage. They aren’t open at rest but start to open as we depolarize the membrane from rest. So at -60 there might be a couple channels opens at -58 there might be 20 channels open and we open more and more till we reach threshold.
  1. What Triggers an AP [S10]
  2. In normal cells the normal trigger for opening of these channels is say a synaptic input or the integration of synaptic inputsby the cell. So how much depolarization came into the cell from a synapse. A little bit of depolarization not enough, but more is definitely enough and we get the full-blown action potential. It doesn’t matter if we get more depolarization because we are already over threshold so the action potential will go.
  3. You can inject current to do this, but physiologically it will be synaptic activation. Threshold is when inward sodium gets to be too much for the outward potassium to overcome and then it certainly goes.
  1. APs are Regenerative [S11]
  2. The reason it is regenerative is this cyclative positive feed-forward loop. A little bit of depolarization opens up sodium channels and sodium comes in and sodium is positively charge and increase depolarization which causes more sodium channels to open. This loop, once beyond threshold, there is nothing to restrain this because it is a feed forward loop. More channels open, sodium comes in, positive charge, depolarize, more channels open, etc. This is the key cycle for the rising phase of the action potential
  1. Learning Objective #1 [S12]
  2. SKIPPED
  1. AP Review [S13]
  2. ANIMATION
  3. You’ve got two gates for the sodium channel, an activation one and an inactivation one. For it to work, once it is inactivated you have to get it back out again.
  1. Learning Objective #2 [S14]
  2. And now comes the part that everybody hates including myself and that is to talk about some of the properties of the membrane that effect how fast and how much things change. If it is intuitively difficult to think about, how electricity flows just think about how water flows. When I turn on the faucet I don’t have to wait for the water in the reservoir water tank to come out of the faucet, the water that is close comes out. It is the same for electricity. Once I start an action potential movement, I don’t have to wait, you don’t have to have diffusion of every ion along the axon to get the electricity to flow, it will flow immediately. Water will flow down the path of least resistance, so if water has a choice of flowing between two pipes and one is narrow and one is a big wide pipe the water will flow faster and you’ll get more water through the big wide pipe. That is really the basis to why we have big fat axon, they have less resistance to current flow just like a big wide pipe has less resistance to water flow. If I punch a bunch of holes in my pipe as the water goes down the pipe, some of it leaks out and we don’t get as much at the end. It is the same with an axon. If a lot of channels are open, some of the current will flow out of the open channels and we will get less depolarization and it won’t go as far. We just talked about resistance and then we have capacitance.
  1. How does an AP Move [S15]
  2. What we do have to understand at the end of this there are two types of propagation. One is in unmyelinated axons and one is in myelinated axons. For the most part myelination goes with making axons bigger or wider diameter because both those things speed up the propagation of action potentials. You will see examples of this when we do the somato-sensory systems. We have these C fibers that are these tiny thin unmyelinated fibers and they are a dull sense of pain and that takes forever. If you whack or pinprick your hand you get an immediate sharp pain, and that goes through small myelinated fibers. But dull achy pain you get afterwards goes through unmyelinated fibers. Proprio-ception and motor neurons for movement, we want those to be fast so those axons we make thick they are fat and we myelinate them.
  1. Resistance= How Far It Can Get [S16]
  2. This should say Length Constant at the bottom of the slide
  3. The only thing we need to worry about now is the diameter of the axon. Because the leaky pipe thing as we will see on Friday only applies to graded synaptic potentials more than action potentials because of the regenerative nature of action potentials. But what does matter for getting any current down an axon or a dendrite is the internal resistance and the membrane resistance and that’s my leaky pipe. If this was water flowing down a pipe and I had lots of holes in the pipe the water would flow out and wouldn’t get there efficiently and if the pipe was narrow not much water could get down the pipe.
  4. In action potential signaling the key thing to think about is the diameter. The length constant is really just how far something goes and its pretty intuitive in this case because if you have a high internal resistance and a small membrane resistance it wouldn’t go very far and this would be a small number. How far something goes down a process depends on those two things. Wide diameter pipe that’s not very leaky will carry water very efficiently.
  5. A standard question is how fast an action potential can go down an axon. The diameter then reflects the internal resistance and it is inverse. The smaller the internal resistance, the larger the diameter.
  1. Fat Axons are Fastest [S17]
  2. Remember that fat axons are fastest.
  1. Capacitance = Speed [S18]
  2. We need to know about capacitance in terms of why axons are myelinated.
  3. Student Question
  4. The strength is not changed by the diameter but the speed is. Here is our axon, you have an action potential here and it moves here and it is not going to change but how fast it gets there depends on the internal resistance. Think of charge or electrons, whatever water will do action potentials will do the same thing. Water goes much faster down a big wide pipe, current will flow faster down a big thick axon. Here is our action potential, we know that it is positive there but down here it is still negative. We tend to talk about positive ions moving but the ions only move across the membrane itself, they don’t go down the axons. Diffusion is efficient over very tiny distances but once you get to millimeters, if you relied on diffusion of sodium ions to go down and start to depolarize you would be dead, you would never get the signal there. If it is negative here, all that means is I have an excess of electrons here as compared to there. The electrons just pass on or jump on spot, they can jump from one ion to another ion. The current flows immediately when they jump. This starts to become more negative and the inside becomes more positive and I get my action potential. The speed occurs because I have a big wide diameter and can therefore have more ion species fill this space and therefore can move faster. If I have room for only a single row of ions I will get less current flow. Less current because less charges will move in a given time in a narrow axon compared to a wide one. Just think about water, it applies directly. Whatever water does, current flowing down a wire or axon will do the same
  5. Back to capacitance, depending on how you think about it, whoever designed the nervous system kind of ran into some problems because they had to come up with myelination.