Intro to Neuroscience, Part 1: EC Gradients

Alright, I've been meaning to get around to this post since I started this blog. So I'm very enthused to finally present you with our opening lecture on Neuroscience: Electrochemical Gradients of Cells.

So let's break this down to the basics. I assume that everyone reading this knows what a cell is. If not, we can start a remedial biology course in the comments thread. I will freely admit, however, that the idea of an "electrochemical gradient" may be a bit more confusing to the neuro-illiterate.

First off, an electrochemical gradient is, for purposes of our discussion, a special type of concentration gradient. This means that we have a membrane, and we have different stuff on each side of it. In terms of a concentration gradient, this could really mean anything. We could have a gallon of distilled water on one side of the membrane, and a gallon of water saturated with food coloring on the other side of the membrane. Now if we were to punch some microscopic holes into this membrane, sized such that the imaginary food coloring could cross it, can you guess what would happen?

That's right, it would diffuse across the membrane. If you need some help visualizing, I recommend the first image at that link.

So that's a basic chemical gradient: a chemical that is forced to be more concentrated on one side of a membrane (or in a membrane-enclosed compartment) than the other. Now, the important thing to remember about this gradient is sort of confusing: to thorougly anthropomorphize things, the chemical "wants" to equalize the gradient on its own, so the energy to promote diffusion is provided by the gradient itself. This is gonna be important in the next chapter, which will come at some point in the near or distant future.

Now things are somewhat more complicated in neurons (and, indeed, in cells in general): the concentration gradient consists of ions, and thus you also have to deal with an electrical potential as well. Exactly how this works is one of the things that often kills people first being introduced to neuroscience, so I'm going to explain this as simply as I can.

The key idea here is that a cell--specifically, in this instance, a neuron--has certain established concentration gradients with respect to certain ions. Because of a difference in the distribution of these ions across the membrane, there is an electrical potential established across the membrane: the interior of the cell is more negative than the exterior of the cell. Since a potential is a comparative value (that is to say, one can't define it in absolute terms but only in reference to something else), the outside of the cell is defined as having a potential of 0 mV, and the potential of the inside of the cell is defined in reference to that value.

Following are some values of the important ion concentrations for an average mammalian neuron. It is important to realize that there can be some wide variation between different neurons, between different compartments of a single neuron, etc. These are just to give you a general idea of what you're looking at here, and are cribbed from my copy of Neuroscience, 3rd ed., by Purves et al (2004):

Potassium (K+): 140 mM (intracellular); 5 mM (extracellular)
Sodium (Na+): 5-15 mM (intracellular); 145 mM (extracellular)
Chloride (Cl-): 4-30 mM (intracellular); 110 mM (extracellular)
Calcium (Ca++): 0.1 nM (intracellular); 1-2 mM (extracellular)

Neurons generally have a resting potential in the range of -40 to -90 mV. This can be calculated based on the ionic concentrations utilizing the Goldman Equation, a variant on the Nernst Equation. I will torture neither you nor myself by attempting to go more into that now, so I think we can agree to just leave it at that.

Now, looking over that list of concentration gradients, I can imagine you might have a few questions. I'll see if I can guess a few:

• Why is the inside of the cell negative, when it has about as much positive stuff inside as outside, and a bunch of negative stuff outside as well?


• How does the cell keep a bunch of those two positive ions on the outside of the cell (calcium and sodium) while keeping a bunch of another one (potassium) inside the cell?


• Why does all this matter to the cell, anyway?

Unfortunately, the answer to all of these is: it's complicated. But I'll do what I can to simplify things.

The simplest answer to the first question is that the most of the stuff inside a cell is negative, especially the DNA. So the potassium inside of the cell mostly serves to balance out the negative charge that lies therein. Also, there's the fact that the potential difference is not very large, in the grand scheme of things, and mostly exists at the membrane itself.

The answer to the last is that neurons communicate in an electric fashion, via action potentials. The electrochemical gradient is essential to enabling the action potentials to occur.

The middle question is where things start to get interesting. Let's start by pointing out that the cell membrane is selectively permeable. In our example of diffusion to explain concentration gradients above, we poked a bunch of imaginary holes in a membrane that would only allow food coloring to pass through. A cell membrane has a bunch of similar holes in it. These are called ion channels. A given ion channel is generally permeable to only one ion, or a class of ions. So it will only allow certain ions to pass through, while excluding others.

But where it gets really interesting is when we start discussing how the cell establishes these ion gradients. It's certainly possible to imagine a cell that just spends all of its time kicking sodium and calcium out of the cell, while bringing potassium in. And there is a lot of that going on, by activities such as the Sodium-Potassium Pump, for example. But that's not the most important thing going on.

Let's start by imagining a pair of compartments, one of which is full of sodium and one of which is full of potassium. This is a viable model of the electrochemical gradient because these are the two main ions participating in action potentials, and the main ions responsible for the electric potential at rest. Although calcium and chloride ions do effect the EC gradient, they take part in more specialized circumstances. It is also important to mention that in the diagrams that follow, the amounts of ion displayed are fairly arbitrary, and should not be seen as representing any value in actual cells in any serious fashion. These compartments are separated by a membrane:



Now, as you can imagine, since the ions in question "want" to diffuse, there's a driving force for both of these ions to go to the other compartment. But so long as they're separated by a membrane, they can't. Now imagine that we were to place two potassium "leak" channels in this membrane, which would allow two-way transfer of potassium ions:



As you can imagine, we would quickly get to the point where potassium was starting to travel over to the other compartment:



But notice something: now that we have more potassium ions in the other compartment, that compartment has started to develop a positive charge. This causes the potassium compartment to develop a negative potential. This is because the positive charges in the one compartment are starting to repel each other. The sodium ions are still trapped in their compartment, so they are forced to stay put. Potassium ions, on the other hand, can travel back to their starting compartment, since these ion channels are two-way:



Note that at this point, the amount of potassium flowing back into the cell is smaller than the amount flowing out. This is because at this point, the concentration gradient is still the primary driving force for net flow of potassium. Although the electrical gradient is reducing the outward flow, it is not the dominant force. Eventually, though, the power of the two gradients equalizes into a dynamic equilibrium:



I should point out that I just realized that my drawing is a bad example because in a real cell there is still much more potassium in the cell than out. But that aside, the key point here is that at this point there is still potassium driven out of the cell by diffusion, and driven back into the cell by charge repulsion. Thus, the net driving force on potassium is zero. The net driving force on sodium, on the other hand, is much greater. But since sodium cannot travel through the potassium leak channels, it is stuck outside of the cell, hammering on the gates.

What happens when the cell opens the door and invites sodium in? The action potential--but that's a story for another day.

Any questions, clarifications? Feel free to post a comment below. I want to make sure I got this right, and I want to make sure you guys understand, because this is the foundation for some of the stuff I'd like to actually dig into later.