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New Chapt 3-Intro action Pot(1)

New Chapt 3-Intro action Pot(1) - Chapter 3 ...

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Unformatted text preview: Chapter 3 Introduction to the Action Potential In the last chapter we showed that cells have a resting potential determined largely, but not exclusively, by the difference in K+ concentration on the inside of the cell and the extracellular fluids in which the cells are bathed. All cells have a high permeability to K+ and a much lower permeability for Na+. The small Na+ permeability, however, produces a constant leakage of positively charged Na+ ions into the cell, which causes the interior of the cell to be less negative than if it were permeable only to K+ and to no other ion. We then showed that the resting potential is accurately predicted by the Goldman, Hodgkin Katz (GHK) equation, an equation similar to, but slightly more complex than, the Nernst equation. The GHK equation takes the concentration gradient of each ion into account but weights the contribution of each ion according to the ion’s relative permeability. Since cells have a resting potential, negative and positive charges are separated by the cell membranes such that the inside of cells have more negative charges than the outside. Thus, resting potentials are about  ­70 mV, inside negative relative to outside. The separation of charges makes each cell a battery. In other words, if a wire, or some other conductive material connected the inside and outside of the cell, electric current would flow and could power a device. The entire theme of this chapter is that the cell’s battery, its resting potential, is the power source that generates action potentials. In order to understand how action potentials are generated, we first need to more carefully explain ion channels, and the special types of ion channels, called voltage gated ion channels, that produce action potentials. Ion channels are proteins in the cell membrane that confer permeability to ions The reason that cells have permeabilities for ions is because they have ion channels inserted into their membranes. Ion channels are proteins with a molecular structure that creates a central pore (the molecular structure of ion channels will be described in a later chapter). The important point is that the pore of each ion channel is selectively permeable to only one ion. It is, therefore, no surprise that neurons, and all other cells, have a large number of ion channels that are selectively permeable to potassium, which is largely responsible for their resting potential. These channels are called K+ channels (Fig. 1). Fig. 1. K+ channels in the membrane are impermeable to Cl ­ and Na+ ions. At the potassium equilibrium potential, Ek, equal numbers of K+ ions leave the cell, driven by the concentration force, as enter the cell, attracted by the electrical force. The movement of K+ ions is through the pores of K+ channels, which only allow K+ ions to pass. 23 If neurons only had K+ channels, their axons could not transmit a signal over long distances with high fidelity, the features that are the hallmarks of an action potential. If anything, the signal would die out at a location close to where it was initially generated and thus the signal would never reach the axon terminal. Without action potentials, signals on an axon disappear a short distance from where they are initiated The reasons for the inability to transmit information over long distances with only K+ channels are illustrated in Fig. 2. The figure shows an axon that has a large number of K+ channels and a normal resting potential of  ­70 mV, inside negative. A short pulse of positive current (a signal) is then injected into the axon at its end on the far left. The pulse inserts a fixed number of positive charges into the axon. Let’s trace what happens to these positive charges (the signal) as they travel down the axon. Fig. 2. Lower panel shows an axon being injected with positive current. The amount of current at the injection site and the loss of current along the axon is indicated by arrows and by thickness of red triangle. There is no change in membrane potential at locations beyond the red triangle because all the injected current has been lost. Graph in top panel plots change in membrane potential as a function of distance along the axon. The first point is that the positive charges injected into the axon are attracted to the negative charges that line the inside of the axon’s membrane. Since charges follow the path of least resistance, the positive charges move initially to the closest negative charges on the membrane and then to the negative charges slightly farther down the axon and so on. The movement of the positive charges then acts to partially neutralize the negative charge (it makes that portion of the membrane less negative than it was before). There are only a limited number of positive charges that were injected, and these could only neutralize the negative charges on a limited length of the axon. There simply are not enough positive charges to move to sites farther down the axon. In other words, as one moves down the 24 axon, the change in membrane potential becomes smaller and smaller until a point is reached along the axon where the membrane potential has not changed at all. From that point on, the axon has no way of knowing that any signal was presented at any place on the axon. But there are also other factors that cause the signal to die out a short distance from the site at which it was initiated. Since the membrane at each point is made less negative, the negative electrical force holding K+ in the cell is reduced. Thus the balance between the electrical force holding K+ in the cell and the concentration force driving K+ out of the cell is changed, where the change provides a larger edge to the concentration force. In short, K+ is driven out of the cells by its concentration force at the sites where the positive current has decreased the negativity inside the cell. What this means is that the signal, the pulse of positive charges injected into the cell, is lost by the efflux of positive charges from the cell interior that are carried by K+ ions. The loss of positive charges from the cell’s interior causes the inside of cell to become more negative, thereby restoring the membrane potential to its normal resting value. The net result of these events is that a signal, an injection of positive charges, delivered to one end of the cell, say at the axon hillock, will cause a depolarization (a decrease in negativity) in the hillock and in the axon segment adjacent to the hillock, where the degree of depolarization will decrease progressively along the axon until a point is reached where no depolarization occurs at all. In addition, the segments that were depolarized, quickly recover to assume a normal resting potential due to the loss of K+ through potassium ion channels. The signal will die out a short distance from the hillock and never reach the axon terminal. Thus the signal could not be conveyed to another cell and the entire idea of communication among cells, the raison d’etre of the nervous system, could not be achieved. Voltage Gated Ion Channels generate Action Potentials How can a signal be generated that does not die out along the axon but rather can reproduce itself along the entire length of the axon so that the same signal that was initially generated at the axon hillock will appear a short time later at the axon terminal? The answer is an action potential. The action potential is created by a new class of ion channels that are opened and closed by the negative charges inside the cell. In the previous section, K+ channels were described that were always open, regardless of the membrane potential. Here I present channels that are gated (opened and closed) by the membrane potential. Such channels are called “voltage gated ion channels”. Two types of voltage gated ion channels generate action potentials. One is a voltage gated sodium channel and the other is a voltage gated potassium channel. Below we first turn to the voltage gated sodium channels, and following an explanation of how they work and what the consequences of their actions are, we will then turn to a similar explanation for voltage gated potassium channels. Voltage gated Sodium Channels Figure 3 shows the essential features of voltage gated sodium channels. The three main features of the channel are: 1) A central pore that is selectively permeable to Na+ ions; 2) A gate that can block the pore, called the activation gate, that is closed at the resting potential but is opened by depolarization (when the inside of the cell becomes less negative than rest); and 3) a second gate, called the inactivation gate, that is open at rest but is closed by depolarization. The inactivation gate is also referred to as a “ball and chain”, as it has a 25 structure such that a length of amino acids forms a chain ­like structure that is linked to another group of amino acids that forms a ball ­like structure. Thus, when neurons are at rest, at about  ­70 mV, the activation gate is closed and the inactivation is open. The whole idea of depolarization is to open the activation gate and close the inactivation gate. However, an important feature of the two gates is that when the axon is depolarized, the opening of the activation gate is just slightly faster than the closing of the inactivation gate, as explained below. The way the channel works is that when the membrane depolarizes, the activation gate opens quickly allowing for the influx of Na+ ions, and a moment later the channel shuts off automatically as the ball swings up and plugs the pore. The channel opens, but only for a fraction of a millisecond, and then closes, automatically by itself. Fig. 3. Voltage gated sodium channels have two gates, an activation and an inactivation gate. Whether each gate is open or closed is determined by the membrane potential. 1: At and around the resting potential, the activation gate is closed and the inactivation gate is open. Because the activation gate is closed, no Na+ ions can enter the cell. 2: When the membrane is depolarized, and thus less negative than at rest, the reduced negativity opens the activation gate, thereby allowing for the influx of Na+ into the cell. 3: After the activation gate has been open for about 1.0 ms, the slower inactivation gate swings shut, thereby plugging the pore and preventing the further influx of Na+ ions into the cell. The closing of the inactivation gate always follows the opening of the activation gate, and acts as a self ­ limiting gate that allows the pore to be open for only about a 1.0 ms and no longer. Figure 4 illustrate both the generation and propagation of an action potential as the gates of the Na+ channels open and close along an axon. We begin at rest (Fig. 4 ­1), when the activation gate is closed and the inactivation gate is open (i.e., the ball is not plugging the pore of the channel). Since the activation gate is closed, Na+ ions are prevented from traveling through the pore, and thus there is no influx of Na+ at rest. A pulse of positive current is then injected into the axon and the positive current depolarizes the membrane (Fig. 4 ­2). The depolarization opens the activation gate, and Na+ ions flow into the cell. Since Na+ is far more concentrated on the outside than the inside of the cell, and the inside of the cell at rest is about  ­70 mV, Na+ ions are driven into the cell by a concentration force and are attracted into the cell by its internal negativity (by an electrical force or attraction). In short, there is a large net force that drives Na+ ions into the cell. Sodium ions bring positive charges into the part of the cell just under the open Na channel. Positive Na+ ions entering the cell cause the portion of the membrane just under the open Na channel to become very positive. Indeed, the membrane potential becomes increasingly positive with the entry of Na+ ions, until it becomes so positive, that for every Na+ ion driven in by the concentration force, a Na+ ion will be repelled out of the cell by the electrical force. In other words, the membrane just under the open Na channel will approach 26 the sodium equilibrium potential, ENa, which is about +55 mV (inside positive). A moment later (in less than 1.0 ms) the depolarization causes the inactivation gate to close, thereby plugging the Na channel and preventing any further influx of Na+ through that channel. Notice what happened in this brief period of less than 1.0 ms (1/1000 of a second); the membrane potential spikes from a resting value of  ­70 mV to +55 mV, a net change of 125 mV! There is now an excess of positive charges under the Na channel. Some of the positive charges are attracted to the negative charges further down the axon (Fig. 4 ­2). When the positive charges reach the downstream portion of the axon, they depolarize that part of the membrane and open the voltage gated Na channels located there. The activation gates on those channels then open, allow the influx of Na+ ions that drives the membrane potential to +55 mV, ENa (Fig. 4 ­3). The inactivation gates then quickly close, ending the influx of Na+ (Fig. 4 ­4). The positive charges at that point then travel down the axon opening the activation gates in those downstream Na channels, causing the membrane potential to spike to +55 mV, and the cycle is then repeated all along the axon, as illustrated in Fig. 4. Fig. 4. Conduction of an action potential by the sequential opening and closing of voltage gated Na channels along the length of the axon. The sequences in panels 1 ­5 are explained in the text. 27 This spike in the membrane potential, from  ­70 to +55 mV, is what comprises the upstroke of the action potential. The action potential is also called a spike because of the quick spike ­ like change in membrane potential. Thus the action potential, or spike, is a stereotyped event that is triggered by depolarization of the membrane. Typically the first depolarization that starts the entire cycle is due to the influx of positive charges caused by the release of transmitter at the synapse. But once the spike or action potential is first initiated at the axon hillock, it is reproduced over and over again at each point along the axon, because voltage gated sodium channels are present along the entire length of the axon. So long as voltage gated Na channels are in the membrane, the action potential will propagate down the axon, whether the axon is only a few hundred micrometers or many meters in length. And the action potential has high fidelity since an open Na+ channel at any point on the membrane drives the membrane potential to ENa, +55 mV. In other words, the same 125 mV change in membrane potential that occurs at the axon hillock, due to the opening of Na channels, also occurs a few moments later at the axon terminal. The Roles of Voltage Gated Potassium Channels The spike in membrane potential does not complete the events that underlie the action potential. The next event is to quickly reset the membrane potential back to its resting value, which then closes the activation gates and opens the inactivation gates of the Na channels so that another action potential can be generated. The rapid re ­polarization of the membrane potential is accomplished by the opening of voltage ­gated potassium channels. Fig. 5. Voltage gated potassium channels. 1: The gate is closed at the resting membrane potential and does not allow K+ ions to pass through the pore. 2: The gate is opened by depolarization, when the inside of the cell becomes less negative. Unlike voltage gated sodium channels, the voltage gated potassium channels do not have an inactivation gate. Here is the problem that the potassium channels solve. After the Na channels have opened, which allowed the influx of Na+ ions and drove the membrane potential to +55 mV, the positive charges that accumulated on the inside of the cell have to be rapidly driven out of the cell. Note that the excess positive charges brought in by Na+ ions will be eliminated from the cell by the efflux of K+ ions. Some of the positive charges are driven from the cell through the non ­voltage gated potassium channels that establish the resting potential. However, there are not enough of those K+ channels in the membrane, so if they were the only channels through which positive charges could leave the cell, it would take tens of milliseconds for the axonal membrane to return to its normal resting potential. This is shown by the slow recovery of the membrane potential in Fig. 4. Thus voltage gated potassium channels are inserted into the axonal membrane and their purpose is for the rapid efflux of positive charges from the inside of the cell to the outside. As shown in Fig. 5, voltage gated potassium channels only have activation gates that are opened by depolarization. The opening of the activation gate, however, is just slightly slower than the opening of the Na+ channel activation gates. The net effect of this delay in 28 the opening of K channels is that when the membrane reaches the height of the action potential (at about +55 mV), the depolarization opens the slower K channels, which then get rid of the excess positive charges in the axon the efflux of K+ ions. Stated differently, Na+ ions depolarize the cell by bringing positive changes into the cell and the cell is repolarized by the loss of K+ ions that take the positive charges out of the cells through the delayed opening of K channels. The reason for that positive charges can be carried in by one ion and removed by another ion is that the opening (or closing) of channels depends ONLY on the charge inside the membrane; the channels do not care which ion carried the charge but only care about the charge polarity inside the cell. VOLTAGE GATED CHANNELS OPERATE THOUGH “EQUAL OPPORTUNITY” CHARGES; they care only about charge and are oblivious to whether the charge was carried by K+, Na +, or Ca++ ions; the voltage gates on the channels do not care which ion carries the charge. Fig. 6. An action potential recorded from the squid giant axon. Lower panel shows the four main phases of the action potential. See text for further explanation. The sequence of five events that generate an action potential are described below and are illustrated by the features of the action potential in Fig. 6 and 7. 1) Depolarization of the membrane causes Na channel activation gates to open, thereby causing an influx of Na+ and quickly driving the membrane potential to +55 mV. 29 2) Repolarization begins less than 1.0 ms after the activation gates open. Repolarization, bringing the membrane potential back to a very negative value, starts as the inactivation gates begin to close and shut off the influx of Na+. A small number of positive charges are lost from the cell through non ­voltage gated potassium channels, so the membrane potential becomes less positive, but just by a very small degree. 3) The rapid phase of repolarization occurs as the voltage gated potassium channels open at about the same time as the inactivation gates are closing in the Na channels. Now the permeability for sodium is virtually zero (because the inactivation gates plug the Na channels) but potassium permeability is exceptionally high under the membrane that had just generated an action potential. For a short moment in time, that patch of membrane is permeable to potassium and only to potassium. There is, therefore, a large efflux of K+, driven by both its concentration force (K+ is more concentrated inside the cell) and its electrical force (the inside of the cell is positive at this time, which drives positively charged K+ ions out of the cell). The efflux of K+ removes so many positive charges that the membrane at that point quickly becomes so negative that for every K+ driven out by the concentration force, one is attracted back into the cell by the large negative membrane potential. Stated differently, because of the massive increase in potassium permeability, the axonal membrane at that location approaches the potassium equilibrium potential, EK. This phase of the action potential is called the undershoot, because the membrane potential “undershoots” the resting potential. i.e., for that brief period the membrane potential is even more negative than the resting potential. Fig. 7. The sequence of the actions of the gates in Na and K channels at each of the 5 phases of an action potential are illustrated in panels 1-5. Each phase is explained in the text. 30 4) The large and rapid re ­polarization causes the gates in both the voltage gated sodium and voltage gated potassium channels to reset; the sodium channel activation gate closes and the inactivation opens while the potassium activation gate activation gate closes. 5) The voltage gated sodium and potassium channels reset and are now ready to generate another action potential while the membrane potential returns to its normal resting value. Axons have a refractory period A noteworthy feature is that after an action potential has occurred, the channels cannot generate another action potential until the gates on the Na and K channels are reset. Stated differently, during an action potential, the axon is refractory for about a millsecond. The reason for the refractory period is easily understood by considering the states of the Na and K channels between positions 3 and 4 in Fig. 7. Imagine that a large pulse of positive charges were somehow injected into the axon at the exact moment when the activation gate of the Na channel was open and its inactivation gate closed and the activation gate of the K channel was open. The positive charges could not generate another action potential at that point because the positive charges could not open the Na activation gate (it is already open) and could not open the inactivation gate, because the inactivation gate is opened by hyperpolarization, not depolarization. Thus the gates could not be opened and therefore there could be no addition influx of Na+ to depolarize the cell. To make matters completely impossible for the generation of an action potential at that moment, any positive charges will be driven from the interior carried by K+ through the voltage gated K channels that are now fully open and a maximally conductive state. That part of the membrane has to wait for an additional fraction of a millisecond. During that period, the large K+ conductance and the loss of K+ ions cause the membrane to approach EK, and hyperpolarize, i.e., become even more negative than rest. The negativity resets the activation and inactivation gates of the Na channels as well as the K activation gates (position 5 in Fig. 7). Now the gates can again respond to a depolarization and generate another action potential. Indeed, the refractory period sets an upper limit on the rate at which action potentials can be produced. Since the refractory period is about 1.0 ms, the highest possible firing rate of any neuron is 1000 spikes/sec. The action potential is an all or none event and has a threshold Each action potential is a stereotyped electrical event because it simply is due to the membrane potential approaching the sodium equilibrium potenial (ENa) and then very quickly reverting back to a negative potential around the potassium equilibrium potential (Ek). Thus an action potential is also an “all or none” event. There are no partial action potentials in which the membrane potential sometimes goes to +25 mV, and other times to +15 mV, and other times only to 0 mV. When an action potential occurs, it always drives the membrane potential to +55 mV. It either is evoked in its full-blown form or it does not occur. As explained previously, action potentials are triggered by membrane depolarizations (when the membrane becomes less negative then it is at rest). However, depolarizations are graded and can be small or large or have any value in between. Neurons, however, need a certain level of depolarization to evoke an action potential, called the “threshold level”. In other words, a small depolarization (small change in the membrane potential) will not trigger an action potential, but as the depolarization becomes progressively larger, a threshold level of depolarization is reached that generates the full-blown action potential. 31 Here is how threshold works. Action potentials are not generated by the opening of a single sodium channel because the opening of a single sodium channel does not bring in enough positive Na+ ions to sufficiently change the membrane potential. Rather, the depolarization needed to generate an action potential is produced by the opening of many sodium channels at the same time. When a nerve is depolarized, the depolarization evokes two competing events. First a few sodium channels open thereby increasing the Na+ current entering the cell. However, there is also an increase the amount of K+ leaving the cell. This occurs because the influx of the positive charges carried by Na+ makes the inside of the cell less negative. This reduces the electrical force holding K+ in the cell, and thus the concentration force drives more K+ out of the cell than it did at a more negative membrane potential. There is a range of small depolarizations where the Na+ entry into the cell, while increased over resting, will still be less than the exit of K+ ions from the cell. This range of depolarizations is referred to as being “subthreshold” because no action potentials are evoked by these small depolarizations. Rather after the small depolarization, the membrane potential returns to rest due to the efflux of K+ ions. There is, however, a certain depolarization where the entry of Na+ is exactly equal to the exit of K+. This represents the unstable equilibrium point known as “threshold”, where the membrane teeters between firing and not firing. If, in the next instant, just one more Na+ enters the cell than K+ leaves, the membrane will be further depolarized by just a tiny amount. That tiny, additional depolarization will then open another Na+ channel that will bring in more Na+ and initiate the positive feedback shown above. The net result is a rapid, nearly simultaneous opening of many sodium channels that drives the membrane potential to the sodium equilibrium potential, ENa, which is an action potential. Conversely, if, in the next instant one more K+ leaves the cell than Na+ enters, the membrane potential will begin to return to the resting value. A definition of threshold for a nerve is, therefore, that value of membrane potential at which the Na+ current entering the cell is equal to the K+ current leaving the cell. For most neurons this is in the range 10 to 15 mV depolarized from rest. 32 ...
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