Action Potential

The Neuronal Membrane at Rest

The Neuron at Rest

The most critical factor in the neuron’s capability to communicate is its ability to fire. How a neuron fires is based upon its electrical properties. This can become a little complicated. So first we must learn about the electrical properties of a nerve cell when it isn’t firing or at rest before we move to what happens when it fires. So, in this lesson we’ll be learning about the neuron at rest.

Protein Channels and the Neuronal Membrane

As mentioned in the previous lesson, the neuron is enclosed in a cell membrane that is made up of a phospholipid bilayer. Because of the fatty nature of this membrane, only compounds that are fat soluble – that is, molecules with no charge - can easily cross it. Charged particles or ions cannot easily cross unless there is a protein channel that will allow them to pass through. Some of these protein channels are always open while some other types can open and close under different circumstances.

The Resting Membrane Potential

It is this very nature of the neuronal membrane that allows it to posses an electrical charge or become polarized. Polarization means that a neuron has a different charge on the inside of the membrane relative to the outside of the membrane. We can measure the voltage of this charge or potential by recording from the inside of the neuronal membrane compared to the outside. When the neuron isn’t firing, we call this charge the resting membrane potential. The resting membrane potential is always negative, meaning there is always a more negative charge on the inside of the neuron. Different neurons at different temperatures can vary in their resting membrane potential but is typically around -70 millivolts (mV). Note that this is a very small charge, for example, a 1.5V flashlight battery is 25 times greater. Nonetheless, we don’t need a lot of charge because what we are powering here is movement of information.

Ions Cause the Membrane to Have a Charge

So, what causes neurons to be polarized? The charge comes from ions which are charged particles or atoms that are charged because they have lost or gained electrons. Recall that particles that are charged are typically water soluble, not fat soluble, and therefore cannot easily cross the cell membrane. Let’s now meet the cast of characters that play a role in the resting membrane potential. First there are two main positively charged ions: sodium ions – abbreviated in chemistry as (Na+) and potassium ions, abbreviated as (K+). Of the negative ions we have chloride ions, abbreviated as (Cl-) plus a mixture of other negatively charged particles that we refer to collectively as organic anions or (A-).

The Two Forces

In a nutshell, the resting membrane potential exists because on the inside of the cell membrane we have more negative ions than positive ions and on the outside the reverse is true. There are two principle forces which cause an ion to flow from one environment to another. First of all, like charges repel each other, just like the two negative ends of a magnet will repel each other, so will two negative ions. This is called electrostatic force, and it is what drives ions to want to flow away from an environment of the same charge and toward an environment of the opposite charge. The other principle is diffusional force. Diffusional force is the simple concept that ions will want to flow away from an environment where there is a high concentration of that specific ion to an environment where there is a relatively low concentration of that ion.

Diffusional and Electrostatic Forces

Chloride Ion Flow

Which way do you think the chloride ions (CI-) will flow when the channels open? Take a moment to think about it then select the button to find out the answer.

If we ignore membrane charge, diffusional force drives chloride (CI-) towards the lower concentration until both sides have the same concentration.

Sodium Ion Flow

Which way do you think the sodium ions (Na+) will flow when the channels open? Take a moment to think about it then select the button to find out the answer.

Electrostatic force drives positively charged sodium ions (Na+) towards the side with the negative charge until diffusional forces balance things out.

The Importance of Potassium Ions

Now that we understand these forces, lets see how this will play out with our ions at the membrane. Looking at this figure under these conditions, there is much more sodium (Na+) and chloride (Cl-) ions outside the membrane compared to inside, while there are more potassium (K+) and anions (A-) inside the membrane relative to the outside. Of course, in this figure nothing is going anywhere because the ions cannot cross the membrane. And at this point the amount of positive and negative ions on the inside and outside are the same, so there is no net charge or polarization. But this is where the fun comes in.

Potassium Ions Allow K+ to Cross the Membrane

The neuronal membrane actually has some protein channels that are selectively permeable to K+. We simply call them potassium channels. They are always open, allowing K+ some permeability through the membrane. I want you to look at the K+ in this diagram and try to guess where the K+ will want to flow based on its diffusional and electrostatic forces. Try to figure this out yourself first.

Forces Acting on K+

Because there is more K+ inside relative to outside, diffusional forces will make the K+ want to flow outward. At this stage, there is no net charge on the membrane, so there are no electrostatic forces acting on potassium ions. So initially, our K+ ions will begin to flow out through the K+ channel. But wait a second, once K+ ions begin to flow out, now there will be more positive charge on the outside and more negative charge on the inside. Now electrostatic forces will kick in and start pushing K+ back inward. Obviously, some happy medium will eventually occur where the diffusional forces pushing K+ out and the electrostatic forces pushing K+ back in will even out or find an equilibrium. The point at which K+ will find this equilibrium and no longer flow in or out of this cell, is about -70 mV. Hey look at that! That’s the same voltage at the resting membrane potential. Now that our neuron has a charge, it is ready to fire.

The Na+/K+ Pump

There is one last concept before we move on, you may ask yourself how does the neuron maintain such differences in ion concentrations across the membrane. As it turns out, this is a very expensive enterprise. To maintain such high concentrations of Na+ outside the neuron and K+ concentrations inside, Mother Nature uses the sodiumpotassium pump. This pump is constantly working to pump three Na+ ions outside the neuron for every two K+ ions it keeps inside. This pump uses metabolic energy to do this. If you remember, the brain as an organ uses up a large share of the body’s energy, well this little pump uses up to 40% of the total energy used by the brain. So, the next time you eat a burger, remember that several bites of it will be used solely to power the sodium-potassium pumps in your brain.

Equilibrium Potentials

Forces Acting on K+

You have already learned that when potassium ions (K+) are allowed to freely cross the membrane, the membrane develops a charge that is close to the resting membrane potential. The charge, or potential of the membrane, when K+ no longer will flow in or out of the cell, is called the equilibrium potential for potassium, or EK. Remarkably, we can predict the charge at which most ions will develop an equilibrium across the membrane.

The Nernst Equation

Firstly, we can always determine the equilibrium potential for a specific ion experimentally. But we can also predict this using a mathematical equation called the Nernst equation. The Nernst equation calculates the charge (in volts) on the membrane when an ion will no longer flow into or out of the neuron. I don’t think it is important that you be able to calculate the Nernst equation for this level course, however, it is important that you understand some of its components.

Temperature (T) is a Variable

For example, in the equation you will notice that T is a variable, here T stands for temperature. Temperature is often very important for biological processes and the equilibrium potential is no exception. If you were to compare one neuroscience textbook to another, you may find that all these texts differ in the value of the resting membrane potential. Some texts list it as -70 mV and other at -65 mV. The reason for the discrepancy is because some neuroscientists use different model organisms to measure the resting membrane potential, and they use different environments that have different temperatures. For example, some measure the resting membrane potential in giant squid axons while others measure it in sea slugs and still others in slices of rodent brain. The point here is that the equilibrium potential, and thus the resting membrane potential, will differ depending on the temperature of the environment.

Ion Concentration

Two other variables that you will notice in the equation are concentration of [X]o and concentration of [X]i. They represent the concentration of the specific ion outside versus the inside, denoted by o versus i, o for outside, i for inside. Obviously, the relative concentrations of the ions inside versus outside the membrane is important for calculating the equilibrium potential of a specific ion.

The Membrane is not Equally Permeable to All Ion Types

Now that we understand some of the variables involved in the equilibrium potential of a specific ion, there are limitations to point out. As you learned, the neuronal membrane is not equally permeable to every ion. For example, there are K+ ion channels that are always open to allow K+ ions to cross, and the membrane is pretty permeable to Clions as well. But at rest, the membrane is not permeable to Na+. Thus, the Nernst equation does not take into account the relative permeability of the membrane for a given ion. Secondly, the Nernst equation can only take into account a single type of ion. As we now know, there are several types of ions at play in creating the resting membrane potential.

The Goldman-Hodgkin-Katz Equation

To reconcile such limitations, we can use the Goldman-Hodgkin-Katz equation (GHK equation). This equation combines the Nernst potentials for the three most important ions in the resting membrane potential; namely K+ ions, Na+ ions, and Cl- ions. In addition, it takes into account the permeability of the membrane for each ion type. This provides us with a final value of the membrane potential, abbreviated as Vm. (Be sure not to confuse this with mV which stands for millivolts).

Equilibrium Potential

The equilibrium potential for K+ ions, or EK, is around -80 mV, and the equilibrium potential for Cl- ions, or ECl, is around -60 mV. Note that at rest, the membrane isn’t very permeable to Na+ ions. Thus, the resting membrane potential is somewhere in-between the equilibrium potential for K+ ions and Cl- ions.

Nernst-Goldman Simulator

It is important that you learn the relationship between the membrane, ion concentrations, permeability, and temperature to understand how the nerve cell can develop a charge and ultimately fire an action potential. This tool is a way to help you better understand this relationship. Take some time to play with the variables using this tool to understand these relationships.

The Action Potential

Ion Concentration When the Ion is at Rest

Let’s review what we learned from the last lesson. when the neuron is at rest, it has sodium, potassium, chloride, and anions both inside and outside the membrane. Because the membrane is somewhat permeable to K+, these ions will flow out of the neuron because of diffusional forces. But eventually, the membrane will develop a charge or potential, and then electrostatic forces will force them back in, until there is an equilibrium, such that K+ neither flows in nor out of the neuron. The point at which K+ reaches this equilibrium is around -70 mV, which is the same as the resting membrane potential.

Voltage-Gated Ion Channels

So, let’s add more characters to our play. The neuronal membrane also contains voltage-gated sodium channels along with voltage-gated potassium channels. These are protein channels that selectively allow sodium or potassium, respectively, to pass through the cell membrane. However, they are different from the potassium channels we learned about earlier, in so far as they are not always open. In fact, these channels only open under very specific circumstances. These channels only open when the cell membrane reaches a specific charge or potential. For example, the voltage-gated sodium channels only open when the membrane is at or around -40 mV. Remember that the resting membrane potential is around -70 mV. So, the membrane would have to become much more positive before these channels will open. When they do, the membrane becomes permeable to Na+ ions. Looking at our membrane at rest, take a moment to figure out what would happen to Na+ ions if the membrane were to become permeable sodium. Are the diffusional and electrostatic forces driving them inside of the neurons or outside?

Ion Flow During an Action Potential

In fact, both electrostatic and diffusional forces would drive sodium ions into the neuron. Because sodium ions have a positive charge, all those sodium ions flowing into the cells would rapidly cause the membrane to go from a negative charge to a positive charge. At this point, once the membrane develops a positive charge, the voltage-gated sodium channels will close, and the voltage-gated potassium channels will now open.

Recall that the potassium channels were learned about in the previous lesson make the membrane only somewhat permeable to potassium ions. Now with the voltage-gated potassium channels open, the membrane is much more permeable, and potassium ions will flow across the membrane more freely. At this point, the voltage-gated sodium channels have closed, and sodium ions can no longer cross the membrane. Because the membrane at this point has developed a positive charge or potential, K+ will want to flow out of the neuron, because both diffusional and electrostatic forces will drive them out. Because of the outward flow of potassium ions, the membrane will again develop a negative charge, as all those positively charged ions flow out.

Restoring the Balance of Ions

Once again, our trusty, yet expensive, sodium-potassium pump kicks in and restores the balance of sodium and potassium ions and restores the resting membrane potential. Ok, so we know a little something about the flow of ions during the action potential. Let’s just stick a pin in that for now and come back to it later.

Membrane Charge During Action Potentials

If we were to place a recording electrode inside the membrane of a neuron while it is at rest, we now know that we would record a potential of about -70 mV. Let’s imagine that we also placed a stimulating electrode nearby. Let’s say we applied some electrical charge to the membrane. As we apply more charge, the membrane becomes more positively charged. Again, from the inside relative to the outside. Once the membrane develops enough of a positive charge, taking it from – 70 mV up to around -40 mV, something dramatic happens. The membrane rapidly becomes positively charged up to about +40 mV. In neuroscience speak, we say it becomes depolarized, and then the membrane rapidly becomes negatively charged again, or repolarized. Notice that the membrane doesn’t go back to – 70 mV, but instead goes a little more negative than that, we call this the overshoot. Eventually, the neuron comes back to its resting membrane potential. This entire event is what we call an action potential. What is happening here is that once we apply enough charge with the stimulating electrode, the membrane reaches its threshold, and it fires. The threshold is the charge at which a neuron will fire. It is also the charge at which the voltage-gated sodium channels will open.

Depolarization

At this point, sodium ions will rapidly flow into the neuron and create a positive charge on the membrane, in other words, the inflow of sodium ions will cause it to depolarize. Once the membrane develops a positive charge, the voltage-gated sodium channels will close, and sodium ions cannot flow across the membrane anymore.

Repolarization

At the same time, the voltage-gated potassium channels will open and now potassium ions will flow out of the cell, causing the membrane to repolarize. They will flow out so much so that the membrane will be slightly more negatively charged than its resting membrane potential.

Overshoot

The voltage-gated potassium channels will now close, and the sodium-potassium pump will restore the balance ions back to their original levels and re-establish the resting membrane potential.

Tetrodotoxin and Voltage-Gated Sodium Channels

Obviously, voltage-gated sodium channels are very important for an action potential to occur, and thus very important for neuronal firing. The toxin, tetrodotoxin, is a chemical that blocks the voltage-gated sodium channels. As you can imagine, blocking the voltage-gated sodium channels would prevent the neurons from being able to fire, and thus be a potent neurotoxin. Tetrodotoxin is contained in the Japanese Pufferfish, which is used in the delicacy “fugu”. This fish is eaten because it produces numbness of the lips and tongue, along with intoxication and light-headedness. This is a byproduct of the toxin shutting down the neurons in the mouth. But be careful, if the sushi chef makes one wrong slice in preparing the fish, you could ingest too much of the toxin and die. Talk about adventurous eating!

Propagation of the Action Potential

The Action Potential and Communication

In the last lesson, we learned the cast of characters involved in the action potential and the role each of them plays. In this lesson, you will learn how the action potential allows neurons to communicate.

Threshold Occurs at the Axon Hillock

Let’s look at our neuronal membrane as it exists along the axon. The point where the axon meets the cell body, or soma is called the axon hillock. Once the membrane at the axon hillock reaches threshold, which we know is around -40 mV, the voltage-gated sodium channels that are adjacent to the axon hillock will open. Once they open, sodium ions will flow into the cell at this point, and cause the membrane to depolarize, or become positively charged. Once the membrane becomes positively charged, the voltage-gated sodium channels a little farther along the axon will now open, and that part of the membrane will depolarize, and so on and so on. You can see now how a slightly positive charge at the axon hillock will cause a depolarization at the axon that will then be propagated along the length of the axon. This happens very rapidly: much, much faster than the blink of an eye.

Improving the Action Potential

Although this process happens very quickly, Mother Nature has found a way to make it more efficient. In order for the action potential to be propagated the way I have described so far; the axon would have to be fairly large – and by fairly large I mean about the width of a hair. This may seem trivial, but if our axons were that large, our heads would have to be about the size of a Volkswagen car to fit all of our axons. Thank goodness Mother Nature found a more efficient way! Also, there would be a lot of sodium and potassium ions flowing across the membrane, which would require our expensive sodium-potassium pumps to work very hard and use up a lot of energy.

Saltatory Conduction

In most mammalian species, the action potential jumps along the axon, a phenomenon we call saltatory conduction. This term comes from the Latin word “saltare” meaning to leap. The neuronal axons are covered in a myelin sheath. Myelin is a fatty substance that insulates the axon, the same way a plastic coasting may insulate a wire. In the central nervous system, the myelin is provided by a type of glial cell, called an oligodendrocyte. We mentioned that earlier, in a previous lesson. In the peripheral nervous system, myelin is provided by a different type of glial cell, called a schwann cell. They both do the same thing, which is insulate the axon electrically. Because the myelin sheath is fatty, it appears white, just like whole milk appears more white than skim milk because of the extra fat.

Action Potentials Happen at the Nodes of Ranvier

In between the sheaths of myelin, are the nodes of Ranvier, and this is where the action happens. Once the axon hillock reaches threshold, it causes the voltage-gated sodium channels to open as we have learned. But because the area farther along the axon is now insulated, there are no channels to open and nowhere for the ions to flow across the membrane. Instead, the now positive charge – or positively charged sodium ions, to be precise - spreads along the interior of the membrane below the myelin sheath. Once they reach the next node of Ranvier, their positive charge will cause the voltage-gated ion channels to open, and the membrane at the node of Ranvier will become depolarized, and so on with the next node of Ranvier. One way to think about salutatory conduction is like a series of explosions having a domino effect along the axon. Myelination of the axon and salutatory conduction allows for our axons to be much smaller and the flow of ions across the membrane to be minimized. So where does the threshold charge at the axon hillock come from? It comes from the membrane of the soma and the dendrites.

Converging Information

As mentioned in an earlier lesson, each neuron receives input from up to about 10 thousand other neurons. Each of these inputs conveys information to that neuron. Most of those inputs basically vote on whether that neuron should fire or not.

Summing Up Excitatory and Inhibitory Inputs

They do this by either causing the membrane of the soma and dendrites to slightly depolarize or not. If the input causes the membrane to slightly depolarize, we call that an excitatory input and if it prevents the membrane from depolarizing, we call it an inhibitory input. Basically, at any given time, these inputs collectively are either exciting or inhibiting the cell membrane of the soma and dendrites. Should they excite, or depolarize, the membrane enough, the charge at the axon hillock will reach threshold and the neuron will fire. A neuron will either fire or it won’t; It never just sort of fires. We call this principle the “All-or-None Law.” The way a neuron conveys its message is that either depolarizes and has an action potential or it doesn’t. In this way, neuronal signaling is binary, much the way that information on a computer is binary – it’s either “go” or “no go”. However, there is another level of complexity in the information a neuron conveys. How rapidly a neuron fires will also convey another level of