Neuron Resting Membrane Potential and how it is created

What is a resting membrane potential?

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Most neurons, when they are at rest, i.e. they are not receiving any input (excitatory or inhibitory), have a stable seperation of charges across their cell membrane. This separation of charges across the membrane is called the resting membrane potential. The separation is such that, the outside of the membrane has a layer of positive (+ve) charges and the inside of the membrane has a layer of negative (-ve) charges. This charges are created by ions. +ve charged ions are called cations and -ve charged ions are called anions.

Now it is important to note that there is a mix of both anions and cations on both side of the membrane. It's just that the net sum of the charges are such that, the outside has more positive charge than the inside of the membrane. For example, if the outside has 10 +ve and 5 -ve charges and the inside has 6 +ve and 8 -ve charges, the outside is 7 charges more +ve than the inside (the outside is +5 and the inside is -2. So 5 - (-2) = +7).

Now, the norm is to always consider the outside as zero charge, and then compare the inside of the membrane to the outside. Since the outside is almost always more positive than the inside, the voltage (or charge difference) across the membrane is almost always going to be -ve. Take the example above. The difference between the outside and inside was 7 charges. Now, if we consider the outside as zero, and the inside is 7 charges more negative than the outside, the voltage difference across the membrane will be -7. It is measured in milivolts (mV). Thus we'll say, tyhe voltage difference across the membrane is -7 mV. This -7 mV is the resting membrane potential of that specific cell.

Now the actual resting potential varies from neuron to neuron, but approximately -60 mV would be a really common resting potential of most neurons in our body.

There are lots of cations and anions both inside and outside the cell contributing to the membrane potential, but there are a few very important ones.

Important cations include potassium (K+), sdium (Na+) and _calcium (Ca2+).- Important anions are chloride ions (Cl-) and organic anions (OA-) There are many different organic anions including some negatively charged plasma proteins, but the sake of simplicity, we'll refer to all of them as OA-.

There are two different forces acting on these ions : electrical gradient and concentration gradient.

In simplest terms, electrical gradient is basically a reflection of the famous old saying of "opposites attract!!" This means, +ve charged ions will try to go to or stay in a -ve charged environment and vice versa. This also means, similar charges will repel. +ve charges will try to go away from another positively charged environment. Thus, as the inside of the cell is negatively charged and the outside is more positive, we can easily identify which direction which of our ions will "want" to move. The cations will try to stay or get inside of the cell and the anions will try to move or stay out of the cell. Simple. Right? You wish!!

As it happens so often in med studies, just when you think you've nailed a concept, there's always this one more thing to mess your head up in ways you couldn't foresee!!!

In come the concept of concentration gradient. Concentration gradient is the desire of our cations and anions to move from a place of high concentration to low concentration. K+ and OA- have higher concentrations inside the cell. Na+, Ca 2+ and Cl- have higher concentrations outside the cell.

Life is very simple for our OA-, Na+ and Ca2+. They know what they want!! For organic anions, both it's electrical gradient and concentration gradient is telling it to go out of the cell. For Na+ and Ca2+, both gradients have given them the green signal to go into the cell.

But K+ and Cl- doesn't have such an easy life. For K+, it's electrical gradient is telling it to stay, but it's concentration gradient is telling it to leave the cell as it's in high concentration inside the cell. Opposite for Cl-. It's concentration gradient is trying to drive it into the cell, but it's electrical gradient desires it to stay outside the cell in a more positively charged environment!!

Alright, let's sum up all we have learned in one image!! (The bigger letters indicate higher concentration and smaller letters indicate lower concentration).

How is this resting membrane potential created?

To understand the development of the resting membrane potential, we'll look at it step by step. But in reality, ALL of what i'm about to explain is actually happening at the same time. So just keep that in mind if you're starting to get a little confused towards the end.

For a moment let's imagine a hypothetical neuron and a hypothetical situation, where there is no membrane potential or charge difference across the membrane (0 on both sides of the membrane) and there is also no concentration difference between the outside and inside for the cations and anions mentioned in the previous section. Everything is same everywhere (Which is why it is a hypothetical situation!! Nothing is ever really the same everywhere!! Not in life, not over the world, neither inside our body).

Like every living cell, the neuron cells are also producing organic anions like proteins, phosphates, etc. This is adding to the pool of the OA- inside the cells and now things are starting to change!! By adding a few extra OA- to the inside the cells, the concentration on OA- inside the cell is beginning to rise. Also adding a few extra -ve charges is starting to make the inside of the cell slightly more negative than the outside. This difference is still very, very small. Maybe -4 or -5 mV. (We are not sure exactly what the value is. These are all hypothetical numbers). Now just this alone is not enough to take the neuron to it's resting membrane potential, but these initial (somewhat imaginary) changes are going to be enough to try to push the OA- outside the cell because now, the inside is both negatively charged and has higher concentration of OA- than the outside. But as it happens in real life, you can't always get what you want. Incidentally, the neuron membrane happen to be impermeable to the organic anions. So even though the electrical and concentration gradients are trying to push the OA- out of the cell, they are not gonna be able to do so.

But this doesn't hold true for the rest of the ions. Because the membrane of the neuron has channels for the rest of the ions, known as leak channels. This means they are able to leak these ions in directions decided by the interaction between the electrical and concentration gradients. However, how easily these ions can cross the membrane through these channels are very different for different ions. These leak channels are open all the time. They not gated and are not opening and closing in response to some kind of stimulus (This is a property of voltage gated channels, which will not be discussed in this post. It will be discussed in the next post when I talk about action potentials of neurons).

On the membrane of the neurons we also have a pump called Na+-K+ ATPase (Sodium-Potassium ATPase). This pump is an active pump and it uses energy in the form of ATP to actively pump 2 K+ ions into the cells from the outside and at the same time 3Na+ ions are pumped out of the cell from the inside. As 2 +ve charges are moving in and 3 -ve charges are moving out and the pump is doing it over and over again, this is going to start making the inside of the cell more and more negative. But the potential difference across the membrane is still quite small, maybe the membrane potential will now reach to around -10mV (still hypothetical numbers). However, the important change that happens now is that the concentration of K+ inside the cell has increased than the outside and the concentration of Na+ has decreased inside the cell compared to the outside of the cell.

Now, this increased concentration gradient will drive K+ out of the cell through the potassium leak channels and the membrane potential (now around -10 mV) will try to drive K+ into the cell. But at this point, the membrane potential is too weak and the concentration gradient is a stronger force, thus more K+ will be moving out of the cell through the leak channels. As more and more K+ are moving out, the membrane potential is becoming more and more more negative and thus a stronger force. The K+ will keep moving out of the cell until the membrane potential becomes negative enough to be a strong enough force to stop this moving of K+ along the concentration gradient. In other the membrane potential i.e. the electrical gradient and the concentration gradient are equal and opposite and this is said to be the equilibrium potential, (Because things are at equilibrium now and there is no net movement of potassium ions into or out of the cell. Whatever movement there is will be in equal amount and opposite direction. What it means is, at equilibrium potential, if one ion moves out along the concentration gradient, the electrical gradient will pull one ion back into the cell). For K+, the equilibrium potential will be somewhere around -70 mV and now this is a large enough potential difference across the membrane for the neuron to function.

It is important to know that it takes only a very few K+ (maybe about 0.01% of the total potassium inside the cell) ions to move out of the cell to create the equilibrium potential so this does not really decrease the concentration gradient significantly, only increases the strength of the electrical gradient.

Now for Na+, both it's concentration and electrical gradient is trying to push it back in to the cell. Now if there was a leak channel which had a very high permeability to sodium, Na+ would keep going into the cell starting to make the inside of the cell less negative and more and more towards the positive. It would keep doing so until there was a reversal in electrical gradient, where the inside of the cell has become so much positive that the electrical gradient is now trying to throw sodium out of the cell (While the concentration gradient is still trying to push Na+ into the cell. Again, not a lot of Na+ needs to move in for this to happen so the concentration inside the cell doesn't significantly increase compared to outside). This will the equilibrium potential and for sodium, the equilibrium potential is somewhere around +50mV, i.e. the inside is now 50 mV more positive than the outside (Remember, the outside is always considered to be at 0).

But as it happens, at resting state, the cell membrane and it's leak channels are much, much, much more permeable to K+ than it is to Na+. In fact, the permeability of Na+ at the resting state in only about 4% of what it is for K+. However, a little Na+ will move into the cell and make that -70 mV slightly less negative and lift it up to around -60 mV, which is usually the resting membrane potential of most neurons.

Because the permeability of the resting cell to K+ is much much higher than it is for Na+, the resting membrane potential is much closer to the equilibrium potential of K+. However neither K+ or Na+ is at their respective equilibrium potential, so there will be a few ions moving here and there along with the NA+-K+ ATPase doing what it does, but at the resting state, this won't making too much of a disturbance to electrical and concentration gradients and everything will be much more stable.

Now recall that the concentration gradient of K+ and Na+ played a big role in creating the membrane potential, for Cl- ions, it's quite the opposite. The membrane potential now developed actually creates the concentration gradient for the chloride ions. The -ve interior of the cell will start to drive Cl- ions out of the cell through it's leak channels (which has a permeability of about 45% of that of K+) and the concentration inside the will now be lesser than the outside.

Normally inside the cell the concentration on Cl- will be maintained at very low levels. The neurons also have a channel called K+-Cl- symporter that will be pushing Cl- out of the cell along with potassium when K+is moving out of the cell along with it's concentration gradient. Generally the equilibrium potential of Cl- is usually similar to that of K+, around -70 mV so it doesn't make too significant of a change to the resting membrane potential.

Neurons also have active mechanisms to get Ca2+ out of the cell to maintain very low concentration inside the cell, the most important mechanism being a channel called Na+-Ca2+ exhanger. This channel harnesses the energy of sodium concentration and electrical gradient and while Na+ is moving into the cell, it pushes Ca2+ out of the cell. Because the permeability of leak channels to Ca2+ is very low at resting state, it's concentration and electrical gradient doesn't significantly affect the resting membrane potential.

Although the concentration gradient of Ca2+ and Cl- ions have a very minimal effect on the resting membrane potential, they do play major roles on other aspects of neuron function.

That's all for today!!

Resources :
Guyton and Hall textbook of Medical Physiology, Twelfth Edition
BRS Physiology, 5th edition
Khanacademymedicine Neuron Physiology

All images except the first image are drawn by me.

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Peace!!