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01_21 1-2 _Lester_


									Neuro: 1:00 - 2:00                                                                                        Scribe: Brittney Wise
Wednesday, January 21, 2009                                                                                Proof: Laura Adams
Dr. Lester                              Resting (membrane) Potential                                                Page 1 of 5
RMP - Resting Membrane Potential; K – potassium; Ca – calcium; Na – sodium

I.     Introduction [S1]: We are going to have a bunch of clinical correlations which will connect to the properties of
       neurons. For example, we will talk about epilepsy (a dysfunction in the electrical signaling of neurons).
II.    Electrical signaling in neurons [S2]
          a. What we are dealing with concerning electrical signaling in neurons is one of their major roles which is to
             transfer info from one part of the brain to the other.
          b. There are just 2 things that we need to know:
                 i. Basics of RMP
                ii. How they propagate the signal from one place to another
          c. (Audio picked up here … it was missing for all that’s before this) So that’s the basic concepts. If it was that
             easy, all we would have to talk about is action potentials. But in order to talk about action potentials we need to
             know something about the resting electrical properties of the cell.
III.   Learning Objectives [S3]
          a. These are the things he wants us to know. We need to understand that cells, neurons in particular, can
             concentrate ions against their passive gradients. The neurons can pump Na ions out and concentrate K in the
          b. We also need to know the one equation we can use to calculate the particular properties of an ion and how that
             contributes to the RMP of a cell. This is the Nernst equation.
          c. We also need to know if we get a change in the concentration of ions or we alter the cells permeability to one
             particular ion.
                 i. This latter one is helpful for understanding disease processes where we have ionic imbalances but also the
                    core principle behind how action potentials work, because when an action potential happens we alter the
                    permeability of the cell, we switch it’s permeability from one ion to another so the ions will change, move
                    down their concentration gradients.
IV.    How familiar are you with resting and active properties of membranes? [S4]
V.     The major ion involved in setting the resting membrane potential is … [S5] - This is an important concept. You
       need to know which ion is the most important one at rest. The answer is potassium (so remember potassium!)
VI.    Learning Objective #1: Explain how the concentration gradient of potassium ions across the membrane gives
       rise to the RMP [S6]
          a. One of the goals here is to see how potassium is important in determining the RMP, because if potassium is not
             regulated correctly you will get major changes in the RMP, which can lead to all sorts of problems affecting
             muscles as well as neurons.
VII.   The RMP [S7] - A video was shown at this link: Http://
          a. It talks about different sides of the membrane have different concentrations of ions (video audio is below)
                 i. Neurons like all living cells are surrounded by a plasma membrane that is impermeable to ions. This
                    property allows neurons to maintain different concentrations of ions between the inside and outside of the
                ii. In a typical mammalian neuron, there is a large difference in the concentration of ions, such as sodium and
                    potassium, between the intracellular and the extracellular environments. In addition, the interior of the
                    neuron has a high concentration of organic anions including proteins and nucleic acids (large negatively
                    charged proteins).
               iii. The plasma membrane is composed of a lipid bilayer. Its hydrophobic nature prevents the diffusion of ions
                    across the membrane.
               iv. The only way ions can move across the lipid bilayer is by passing through specialized channels. These
                    channels are transmembrane pores that permit the movement of particular ions while excluding others.
                    Such channels can be in an open or close state.
                v. When a neuron is at rest, most ion channels are closed. However, some potassium channels (blue) are
                    open, permitting potassium ions to diffuse out of the cell down their concentration gradient. Note that
                    sodium channels are normally closed, and thus sodium ions cannot cross the membrane when the neuron
                    is at rest.
               vi. In a typical neuron, the internal concentration of potassium is higher than the external concentration. 2
                    opposing forces influence the movement of potassium. First, a diffusion force drives potassium ions down
                    their concentration gradient towards the exterior of the cell.
              vii. The movement of potassium ions out of the cell increases the internal negative charge. The positively
                    charged potassium ions are attracted to the integral negative charge, and this ELECTRICAL force pulls
                    potassium ions back into the cell.
Neuro: 1:00 - 2:00                                                                                             Scribe: Brittney Wise
Wednesday, January 21, 2009                                                                                     Proof: Laura Adams
Dr. Lester                                          Resting (membrane) Potential                                         Page 2 of 5
           viii. The diffusion and electrical forces eventually come into balance, and an electrical potential, or voltage, is
                  reached at which the electrical force exactly balances the diffusion force. At this point, there is no NET
                  movement of potassium into or out of the cell.
             ix. The electrical potential across the membrane can be measured by inserting an electrode into the cell. A
                  neuron at rest has a voltage difference of about -60 millivolts across the membrane. This value is the
                  neurons’ resting membrane potential and it governed by the relative concentration of ion species between
                  the intracellular and extracellular space.
        b. If you understand what the video is saying that’s the main concept of the RMP. Note that he said if you put an
           electrode in and you measure the RMP and it’s governed by the concentrations of ions and their relative
           permeability’s but it turns out that it’s potassium is the main one, because at rest you mainly have channels that
           are open to potassium and nothing much else. The RMP is close to what would be the equilibrium or Nernst
           potential for potassium.
VIII. The membrane acts to … [S8]
        a. There are really only 2 things you need to know about what the membrane does with respect to ion balance:
               i. The first thing is that it needs to have pumps because it needs to pump ions against what their
                  concentration gradients would have them be at. If you had a membrane that was permeable to potassium,
                  potassium would always tend to come down its concentration gradient. So you would eventually run out of
                  your gradient so you need to be able to pump it against its gradient.
                       1. This is just one of the sodium potassium pumps which pump Na out of the cell so Na is higher
                          outside of the cell and K is higher inside the cell.
              ii. The membrane also needs to be selectively permeable to particular ions. You can have channels open
                  that just let K through or Na and it can control those, so at different times or different conditions it may open
                  and close certain channels.
IX. Comparing initial conditions to conditions at equilibrium: [S9]
        a. This is his walk through version of the animation:
               i. The concept of RMP, all you really need are 2 different solutions, one inside the cell and one outside the
                  cell, and have different concentrations of ions (or a salt really). For example, we have high K (or a high K
                  salt) here (in the left diagram) and a low concentration of K salt there (didn’t catch where he was pointing).
                  Basically a neuron pumps more K into the cell than outside. If you now open up K channels the channels,
                  the K is going to want to leave the cell (cause there is more potassium inside the cell) leaving behind
                  negative anions. It’s the excess of negative charge that attracts the K back in. So you have a chemical
                  gradient and then you’ve got an electrical gradient in the opposite direction. When those 2 are balanced
                  that’s the equilibrium potential or the Nernst potential for that particular anion.
        b. It will work out that K is around -60 which is close to the RMP.
X. Electrical difference … IN vs. OUT [S10]
        a. The neuron is the blue fish looking structure. You can put an electrode in the neuron (yellow arrow is an
           electrode) and measure that potential across the cell: when you put an electrode in you can see that we
           measure a -70 (which is the RMP). You can take it out and put it back in there: it will sit there and that’s the
           RMP. It needs that in order to be ready to generate action potentials.
        b. So, if there is not RMP you will not get any electrical signaling in the cell.
        c. Electrical difference … IN vs. OUT [S11]
               i. This second slide is showing what would happen with the electrode in.
XI. Can we calculate the potential? [S12]
        a. This is the one equation that we all should be familiar with. You won’t be asked to recall the equation during a
           test but you should know how to use it.
               i. Nernst equation this relates the chemical and the electrical gradient (he will give us a simplified version to
                  show you how to calculate this because on the take home test there will be some example questions you
                  need to work through on this).
XII. Learning Objective #2 – Compute the equilibrium potential of an ion using the Nernst equation [S13]
XIII. The Nernst potential for K- [S14]
        a. This is the original form of the equation; you know with the gas constant, temperature, Faraday’s constant, z is
           the valance of the ion. So apart from calcium that’s going to be 1, but it is going to flip positive and negative
           depending on whether you have chloride or potassium.
        b. This form is the most useful because it’s an approximation. It’s perfectly ok to generalize an approximate, and
           make this a more simple form so it’s easy to calculate.
        c. People will tell you a RMP is -60, well it might be that in a particular cell and it might be -90 in another cell. But
           it’s in the negative range, down there from like -60 to -90. The simplest form is really to convert this from natural
           to log base 10, and that just makes our calculations pretty easy and you see how they work. Then this becomes
           60 over the valence.
Neuro: 1:00 - 2:00                                                                                         Scribe: Brittney Wise
Wednesday, January 21, 2009                                                                                 Proof: Laura Adams
Dr. Lester                                        Resting (membrane) Potential                                       Page 3 of 5
             i. You might have an example (pretty realistic) where there is 10 fold more potassium inside the cell than
                outside the cell. So, this simply become log(10/100) or log(0.1) which will turn out to be (-1). (-1) times 60
                is -60. So this would be the Nernst potential for potassium under those conditions where there is about 10x
                more potassium inside the cell that outside the cell.
            ii. Then you could ask what would happen if you changed the potassium outside the cell or inside the cell,
                what would happen to the cell membrane potential? Would it depolarize and become less negative or
                hyperpolarize and become more negative?
XIV.         If we lowered the [K-] out 10-fold to 1mM, the RMP would … [S15]
      a. It turns out if you lower potassium you would hyperpolarize the cell. So, keeping your potassium outside lower
          is going to make you more negative.
XV. The Nernst potential for K- [S16]
      a. For example, we have lowered it from 10mM to 1mM outside, keep the same inside, this then becomes (-2) and
          we have now hyperpolarized the cell and made it more negative.
      b. Now, for normal physiology it’s important to keep the cell in a reasonable range, because if we are too
          hyperpolarized we are going to be too unexcitable and we are not going to be able to get to threshold for action
      c. So, too negative, hypokalemia, is not good. As is hyperkalemia, too much potassium, cells are depolarized and
          over excitable, lead to things like cardiac problems, arrhythmias, potentially seizure activity (too excitable, we’ve
          got synchronous activity of neurons), so we want to keep our potassium in a reasonable range. This is why
          (going back to the cytology lecture) one of the key functions of astrocytes is to make sure that potassium doesn’t
          get elevated after too much electrical activity, because as we will see in the next hour, if we fire a whole bunch
          of action potentials, a lot of potassium will leave the cell and because the extracellular space is narrow (small)
          and because potassium is low outside, it doesn’t start to take that many potassium ions to leave to change that
          potassium concentration. So, again think of this in terms of how glia and neurons function to maintain
          potassium in that low/few mM range.
XVI.    Learning Objective #3 – Predict the effect of changing the concentration of an ion (or its relative
    permeability on the membrane potential [S17]
      a. We’ve done the first part of this learning objective #3, changing the concentration of the ion.
      b. Basically, you will see from some of the examples on the take home test, it doesn’t really matter what ion he
          gives you as long as you know what concentration it is inside and out you can plug it into that equation.
      c. He plugged in potassium, but you could try and plug in sodium and or chloride. You could try to plug in calcium,
          but it is very tightly buffered inside the cell that it’s equilibrium potential is way positive.
      d. The ones that he will ask us questions about, and the ones that we really only need to know about for the most
          part are sodium (Na), potassium (K), and chloride (Cl). These are going to be the most important ions that
          govern the electrical properties of cells.
XVII. Other ions affect RMP [S18]
      a. These are some general points that we should know about membranes:
             i. Different ions have different distributions. So, we’ve seen that the cell keeps potassium high inside and low
                outside. For other ions, it does different things. It keeps sodium low inside and high outside and chloride
                depends on the cell.
      b. The first 2 bullets on this slide are the first 2 properties that he gave us early on about what a membrane needs
          to do. It’s not uniformly permeable or leaky to all ions. So, at rest we have a bunch of potassium channels that
          are open, so potassium is free to move in and out. Of course, it will carry on moving in and out until its
          electrochemical gradients balance, but for the most part it’s going to sit there at -60 unless we disturb the
          situation by opening up other channels for example. So, mainly potassium.
      c. The more general point is that different cells have, as we mentioned, have different RMP’s. Some cells, glial
          cells or some astrocytes can be -40 and be at RMP. Some muscle cells can be at -90. All we are doing is
          adding other channels for different ions in and changing the RMP slightly.
      d. If we had pure potassium, our RMP would equal the Nernst potential for potassium.
XVIII. Concentrations of other ions … [S19]
      a. These are more realistic values, so the Nernst potential for potassium in a realistic neuron is pretty close to -
          100. Most neurons don’t have a RMP near -100.
      b. So, this tells you that if the RMP is not the same as the potassium, then there are other ions moving in and out
          of the cell. That is a guarantee that tells you that.
      c. He has given us Na and Cl on this slide. Na is way up there and Cl is pretty close to potassium.
XIX.    General rule(s) [S20]
      a. So, some people find this useful and some people don’t. He likes to draw a diagram when he is answering or
          trying to work out which direction ions are moving in or where the RMP is or how the membrane potential will
          change if you change the permeability of the ion.
Neuro: 1:00 - 2:00                                                                                        Scribe: Brittney Wise
Wednesday, January 21, 2009                                                                                Proof: Laura Adams
Dr. Lester                                         Resting (membrane) Potential                                     Page 4 of 5
             i. He drew a line as if it were on the y-axis of a graph and labeled it voltage (mV are the units).
            ii. So the membrane potential was represented by the y-axis. So, on this we can draw all of our equilibrium
                potentials. We can start off with RMP down around -60 or so. And then we can add:
                      1. chloride equilibrium potential at -90
                      2. potassium at -98
                      3. sodium at +67
           iii. So, this is just a graphical representation of the data in the last slide’s table.
      b. We can see that RMP is a little more positive than K. This tells us that there are other ions are contributing to
          the RMP.
             i. We have a little contribution from Cl, which is more depolarized so that’s going to tend to push it towards Cl
                a little bit.
            ii. We even have some Na permeability that’s going to let it drift up a little more.
           iii. So basically, when we say relative permeability, that means that most of our permeability is due to
                potassium, so it’s close to potassium but there are some other permeability’s. This is how different neurons
                and different cells can shift their RMP. They just let a few other ions cross the membrane.
      c. The equilibrium potential is obviously the potential at which the membrane is undergoing no net flow of the
          particular ion, and so the membrane potential equals the Nernst potential. For example, if we took the
          membrane potential to +67, and we were able to keep it there, there would be no net movement of sodium now.
          Sodium couldn’t move because the membrane potential is already at its equilibrium potential (if the membrane
          was just permeable to sodium).
      d. The main concept to come from this is that if you can understand this diagram you can understand how not only
          RMP functions but you can understand the action potential. All an action potential is, is changing the relative
          permeability of ion.
      e. So if a cell is sitting at RMP, and we suddenly open up a ton of sodium channels, way more than the potassium,
          the membrane potential will tend to go towards the equilibrium for the particular ion that dominates. If we want
          the membrane potential to be positive all we have to do is open up a bunch of sodium channels, and if they
          dominate the permeability of the membrane, that’s where the membrane potential will go to. This is really the
          basis for excitability in neurons.
             i. If we wanted to bring it back down, we would just (1) open up a bunch of potassium channels or (2) close
                the sodium channels and then the membrane potential would repolarize and be back to normal. You can
                do this for any ion, any situation (you can say open up these channels, close those channels) and you will
                change the membrane potential.
      f. Sometimes you will hear people refer to things like driving force. The driving force on a particular ion is how far
          away it is from the RMP. This is going to give you a clue as to what’s going to happen. If you open up a whole
          bunch of sodium channels, there is a big driving force, and by that he means sodium has a big potential to move
          across the membrane, and it’s going to move into the cell as they membrane potential goes toward the
          equilibrium potential to sodium. Big driving force.
      g. If the membrane potential ends up at the sodium equilibrium potential, now there is a big driving force on
          potassium. If you open up potassium channels it will rapidly move down as potassium leaves the cell.
      h. These concepts are important for knowing how neurons control their excitability.
XX. Ion flux explanation [S21]
      a. Driving force, again, is this difference and it’s obviously going to be due to its electrochemical gradient.
      b. The Nernst equation relates the electrical and chemical gradients. You need to know the concentrations of ions
          on either side, and basically the only other thing that you need to know is if there is a 10-fold change in the
          concentration of ion, there will be a 60mV change. So if you change the ion concentration 10-fold we will have a
          60mV change, IF there are channels open for that ion.
      c. The only other equation that’s useful to know here, and that’s Ohm’s law (V=IR).
      d. We explained the concept of driving force, the difference between the equilibrium potential for the ion and its
          membrane potential, and that’s our voltage. That’s the potential that’s going to drive an ion across the
          membrane or not.
      e. He has just transformed the equation on this slide because it is easier if we want to talk about ionic current. (I –
          the letter i) is our variable, R (this is 1/conductance), and he is using conductance because resistance is kind of
          hard to picture, but conductance can be directly related to the number of open channels that you have. So
          bigger conductance means that you have more potassium channels open.
      f. Ohm’s law becomes the current = the conductance (or the number of channels open) times the potential.
      g. What this means is that here is our driving force. If we have a big driving force on sodium, how come the
          membrane potential doesn’t rest at sodium?
             i. It doesn’t rest at the sodium equilibrium potential because there are no channels open for that ion. So, the
                current due to sodium is zero or very few (no channels open) and so it doesn’t get very far.
Neuro: 1:00 - 2:00                                                                                      Scribe: Brittney Wise
Wednesday, January 21, 2009                                                                              Proof: Laura Adams
Dr. Lester                                       Resting (membrane) Potential                                       Page 5 of 5
            ii. Likewise, if there is no driving force, it doesn’t matter how many channels you have open. For example, if a
                membrane is just permeable to potassium and we are at RMP, there is no net current flowing into or out of
                the cell, it’s all balanced because we have no driving force for potassium once we are sitting at its
                equilibrium potential.
           iii. You need a driving force and you need channels open and then you can change the membrane potential.
      h. If you try and go back to the original concept of how the potassium concentrations differ on different sides of the
          membrane, and then you let diffuse down its concentration gradient until its electrical gradient pulls it back in,
          that’s your Nernst potential and that’s the basis of your RMP. And then these other concepts about how if you
          change potassium you can then change the membrane potential, and this other concept that different ions have
          different distributions across the membrane and if you change channels that allow them to flow in and out of the
          cell you can then change the membrane potential quite dramatically and rapidly.
      i. That latter point is then the basis for the action potential.

[end 29:34]

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