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Kurs: Biologia > Rozdział 33

Lekcja 2: Neuron i układ nerwowy

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How the resting membrane potential is established in a neuron.

Kluczowe punkty:

A resting (non-signaling) neuron has a voltage across its membrane called the resting membrane potential, or simply the resting potential.
The resting potential is determined by concentration gradients of ions across the membrane and by membrane permeability to each type of ion.
In a resting neuron, there are concentration gradients across the membrane for ${Na}^{+}$ ‍ and $K^{+}$ ‍. Ions move down their gradients via channels, leading to a separation of charge that creates the resting potential.
The membrane is much more permeable to $K^{+}$ ‍ than to ${Na}^{+}$ ‍, so the resting potential is close to the equilibrium potential of $K^{+}$ ‍ (the potential that would be generated by $K^{+}$ ‍ if it were the only ion in the system).

Wstęp

Suppose you have a dead frog. (Yes, that's kind of gross, but let's just imagine it for a second.) What would happen if you applied an electrical stimulus to the nerve that feeds the frog's leg? Creepily enough, the dead leg would kick!

The Italian scientist Luigi Galvani discovered this fun fact back in the 1700s, somewhat by accident during a frog dissection. Today, we know that the frog's leg kicks because neurons (nerve cells) carry information via electrical signals.

How do neurons in a living organism produce electrical signals? At a basic level, neurons generate electrical signals through brief, controlled changes in the permeability of their cell membrane to particular ions (such as

{Na}^{+}

and

K^{+}

). Before we look in detail at how these signals are generated, we first need to understand how membrane permeability works in a resting neuron (one that is not sending or receiving electrical signals).

In this context, permeability refers to the ability of a particular molecule to cross the plasma membrane of a cell by diffusion.

If a molecule can cross the membrane, the membrane is said to be permeable to that molecule.
If a molecule cannot cross the membrane, the membrane is not permeable (is impermeable) to that molecule.

Permeability also comes in degrees. That is, a membrane may be more permeable to one type of molecule than another (even though it is "permeable" to both). If a membrane is more permeable to a molecule, it’s easier for that molecule to diffuse across the membrane. If a membrane is less permeable to a molecule, it’s harder for that molecule to diffuse across the membrane.

In this article, we'll see how a neuron establishes and maintains a stable voltage across its membrane – that is, a resting membrane potential.

The resting membrane potential

Imagine taking two electrodes and placing one on the outside and the other on the inside of the plasma membrane of a living cell. If you did this, you would measure an electrical potential difference, or voltage, between the electrodes. This electrical potential difference is called the membrane potential.

Like distance, potential difference is measured relative to a reference point. In the case of distance, the reference point might be a city. For instance, we can say that Boston is

190

miles

northeast, but only if we know that our reference point is New York City.

For a cell’s membrane potential, the reference point is the outside of the cell. In most resting neurons, the potential difference across the membrane is about

30

90

mV

mV

1 / 1000

of a volt), with the inside of the cell more negative than the outside. That is, neurons have a resting membrane potential (or simply, resting potential) of about

- 30

mV

- 90

mV

Because there is a potential difference across the cell membrane, the membrane is said to be polarized.

If the membrane potential becomes more positive than it is at the resting potential, the membrane is said to be depolarized.
If the membrane potential becomes more negative than it is at the resting potential, the membrane is said to be hyperpolarized.

All of the electrical signals that neurons use to communicate are either depolarizations or hyperpolarizations from the resting membrane potential.

Where does the resting membrane potential come from?

The resting membrane potential is determined by the uneven distribution of ions (charged particles) between the inside and the outside of the cell, and by the different permeability of the membrane to different types of ions.

Types of ions found in neurons

In neurons and their surrounding fluid, the most abundant ions are:

Positively charged (cations): Sodium ( ${Na}^{+}$ ‍) and potassium ( $K^{+}$ ‍)
Negatively charged (anions): Chloride ( ${Cl}^{-}$ ‍) and organic anions

In most neurons,

K^{+}

and organic anions (such as those found in proteins and amino acids) are present at higher concentrations inside the cell than outside. In contrast,

{Na}^{+}

and

{Cl}^{-}

are usually present at higher concentrations outside the cell. This means there are stable concentration gradients across the membrane for all of the most abundant ion types.

How ions cross the membrane

Because they are charged, ions can't pass directly through the hydrophobic ("water-fearing") lipid regions of the membrane. Instead, they have to use specialized channel proteins that provide a hydrophilic ("water-loving") tunnel across the membrane. Some channels, known as leak channels, are open in resting neurons. Others are closed in resting neurons and only open in response to a signal.

Some ion channels are highly selective for one type of ion, but others let various kinds of ions pass through. Ion channels that mainly allow

K^{+}

to pass are called potassium channels, and ion channels that mainly allow

{Na}^{+}

to pass are called sodium channels.

There are chloride channels that allow

{Cl}^{-}

ions to cross the plasma membrane, though we won't focus much on them in this article. The chloride channels are conceptually similar to the sodium and potassium channels described in the section above.

The situation is different for organic anions present in the interior of the cell. Often, these anions are negatively charged amino acid side chains in proteins. The proteins are typically large and bulky and remain trapped inside the cell. Thus, organic anions generally cannot cross the membrane like

{Na}^{+}

and

K^{+}

In neurons, the resting membrane potential depends mainly on movement of

K^{+}

through potassium leak channels. Let's see how this works.

What happens if only $K^{+}$ ‍ can cross the membrane?

The membrane potential of a resting neuron is primarily determined by the movement of

K^{+}

ions across the membrane. So, let's get a feeling for how the membrane potential works by seeing what would happen in a case where only

K^{+}

can cross the membrane.

We'll start out with

K^{+}

at a higher concentration inside the cell than in the surrounding fluid, just as for a regular neuron. (Other ions are also present, including anions that counterbalance the positive charge on

K^{+}

, but they will not be able to cross the membrane in our example.)

For clarity, the diagrams in this section show only

K^{+}

and the anions (negatively charged ions) that counterbalance the positive charge on

K^{+}

. We don't say exactly what types of anions these are, so some of them may be

{Cl}^{-}

ions.

Many other ions that are not shown in the diagram may be present in the system, including

{Cl}^{-}

and

{Na}^{+}

. However, since these ions cannot cross the membrane, they will not influence the membrane potential. This is why we can ignore them as we focus on the special case where the membrane is permeable only to

K^{+}

If potassium channels in the membrane open,

K^{+}

will begin to move down its concentration gradient and out of the cell. Every time a

K^{+}

ion leaves the cell, the cell's interior loses a positive charge. Because of this, a slight excess of positive charge builds up on the outside of the cell membrane, and a slight excess of negative charge builds up on the inside. That is, the inside of the cell becomes negative relative to the outside, setting up a difference in electrical potential across the membrane.

For ions (as for magnets), like charges repel each other and unlike charges attract. So, the establishment of the electrical potential difference across the membrane makes it harder for the remaining

K^{+}

ions to leave the cell. Positively charged

K^{+}

ions will be attracted to the free negative charges on the inside of the cell membrane and repelled by the positive charges on the outside, opposing their movement down the concentration gradient. The electrical and diffusional forces that influence movement of

K^{+}

across the membrane jointly form its electrochemical gradient (the gradient of potential energy that determines in which direction

K^{+}

will flow spontaneously).

Eventually, the electrical potential difference across the cell membrane builds up to a high enough level that the electrical force driving

K^{+}

back into the cell is equal to the chemical force driving

K^{+}

out of the cell. When the potential difference across the cell membrane reaches this point, there is no net movement of

K^{+}

in either direction, and the system is considered to be in equilibrium. Every time one

K^{+}

leaves the cell, another

K^{+}

will enter it.

The equilibrium potential

The electrical potential difference across the cell membrane that exactly balances the concentration gradient for an ion is known as the equilibrium potential. Because the system is in equilibrium, the membrane potential will tend to stay at the equilibrium potential. For a cell where there is only one permeant ionic species (only one type of ion that can cross the membrane), the resting membrane potential will equal the equilibrium potential for that ion.

The steeper the concentration gradient is, the larger the electrical potential that balances it has to be. You can get an intuitive feeling for this by imagining the ion concentrations on either side of the membrane as hills of different sizes and thinking of the equilibrium potential as the force you'd need to exert to keep a boulder from rolling down the slopes between them.

If you know the

K^{+}

concentration on both sides of the cell membrane, then you can predict the size of the potassium equilibrium potential.

Does membrane potential equal $K^{+}$ ‍ equilibrium potential?

In glial cells, which are the support cells of the nervous system, the resting membrane potential is equal to the

K^{+}

equilibrium potential.

In neurons, however, the resting membrane potential is close but not identical to the

K^{+}

equilibrium potential. Instead, under physiological conditions (conditions like those in the body), neuron resting membrane potentials are slightly less negative than the

K^{+}

equilibrium potential.

What does that mean? In a neuron, other types of ions besides

K^{+}

must contribute significantly to the resting membrane potential.

Suppose that you did an experiment in which you measure the resting membrane potential of a glial cell while systematically changing the

K^{+}

concentration of the extracellular fluid. If you did this and graphed the results, you would find that the resting membrane potential of the glial cell was consistently equal to the potassium equilibrium potential. That suggests that, in glial cells, the resting membrane potential is determined solely by the resting permeability to

K^{+}

If you repeated the experiment with a neuron, you would find that the measured resting membrane potential was close to the potassium equilibrium potential, but deviated from it a bit (especially when the concentration of

K^{+}

outside the cell was low). The resting membrane potential under physiological conditions is less negative than the potassium equilibrium potential. This tells us that, for neurons, the

K^{+}

permeability and

K^{+}

concentration gradient are not the only factors that determine the resting membrane potential.

Both $K^{+}$ ‍ and ${Na}^{+}$ ‍ contribute to resting potential in neurons

As it turns out, most resting neurons are permeable to

{Na}^{+}

and

{Cl}^{-}

as well as

K^{+}

. Permeability to

{Na}^{+}

, in particular, is the main reason why the resting membrane potential is different from the potassium equilibrium potential.

Let’s go back to our model of a cell permeable to just one type of ion and imagine that

{Na}^{+}

(rather than

K^{+}

) is the only ion that can cross the membrane.

{Na}^{+}

is usually present at a much higher concentration outside of a cell than inside, so it will move down its concentration gradient into the cell, making the interior of the cell positive relative to the outside.

Because of this, the sodium equilibrium potential—the electrical potential difference across the cell membrane that exactly balances the

{Na}^{+}

concentration gradient—will be positive. So, in a system where

{Na}^{+}

is the only permeant ion, the membrane potential will be positive.

In a resting neuron, both

{Na}^{+}

and

K^{+}

are permeant, or able to cross the membrane.

${Na}^{+}$ ‍ will try to drag the membrane potential toward its (positive) equilibrium potential.
$K^{+}$ ‍ will try to drag the membrane potential toward its (negative) equilibrium potential.

You can think of this as being like a tug-of-war. The real membrane potential will be in between the

{Na}^{+}

equilibrium potential and the

K^{+}

equilibrium potential. However, it will be closer to the equilibrium potential of the ion type with higher permeability (the one that can more readily cross the membrane).

The membrane potential is a weighted mean of the equilibrium potentials of the different permeant ions.

If only one permeant ionic species is present, the membrane potential will be determined by that ion's equilibrium potential. It doesn't matter how permeable it is (how readily it can cross the membrane), because there is nothing to counter it.

If multiple permeant ionic species are present (and not at equilibrium), the resting potential will be between the equilibrium potentials for the different permeant ions. The greater the permeability to a given ionic species, the more it will dominate the final membrane potential.

For the membrane potential to be constant, the

{Na}^{+}

current has to equal the

K^{+}

current (assuming

{Cl}^{-}

is at equilibrium, which is reasonable in many cells). Current equals permeability times driving force (driving force is the difference between the membrane potential and the ion's equilibrium potential), which is essentially Ohm's law. If the permeability to one ion is much greater than that of the other, the driving force has to be less (i.e., the membrane potential must be closer to that ion's equilibrium potential) in order for the currents to be equal.

Opening and closing ion channels alters the membrane potential

In a neuron, the resting membrane potential is closer to the potassium equilibrium potential than it is to the sodium equilibrium potential. That's because the resting membrane is much more permeable to

K^{+}

than to

{Na}^{+}

If more potassium channels were to open up—making it even easier for $K^{+}$ ‍ to cross the cell membrane—the membrane would hyperpolarize, getting even closer to the potassium equilibrium potential.
If, on the other hand, additional sodium channels were to open up—making it easier for ${Na}^{+}$ ‍ to cross the membrane—the cell membrane would depolarize toward the sodium equilibrium potential.

Changing the number of open ion channels provides a way to control the cell’s membrane potential and a great way to produce electrical signals. (We will see the opening and closing of channels again when we discuss action potentials.)

The ${Na}^{+}$ ‍- $K^{+}$ ‍pump maintains ${Na}^{+}$ ‍ and $K^{+}$ ‍ gradients

The

{Na}^{+}

and

K^{+}

concentration gradients across the membrane of the cell (and thus, the resting membrane potential) are maintained by the activity of a protein called the ${Na}^{+}$ ‍- $K^{+}$ ‍ ATPase, often referred to as the sodium-potassium pump. If the

{Na}^{+}

K^{+}

pump is shut down, the

{Na}^{+}

and

K^{+}

concentration gradients will dissipate, and so will the membrane potential.

At the resting membrane potential of a neuron, neither

{Na}^{+}

nor

K^{+}

is at its equilibrium potential. The membrane potential is less negative than the

K^{+}

equilibrium potential, but less positive than the

{Na}^{+}

equilibrium potential. Thus, there will be a steady leak of

K^{+}

out of the cell and of

{Na}^{+}

into the cell. The activity of the pump opposes these leaks and maintains the ions' concentration gradients.

In addition, the pump also has to deal with the

{Na}^{+}

and

K^{+}

that cross the membrane when a neuron fires an action potential.

Like the ion channels that allow

{Na}^{+}

and

K^{+}

to cross the cell membrane, the

{Na}^{+}

K^{+}

pump is a membrane-spanning protein. Unlike potassium channels and sodium channels, however, the

{Na}^{+}

K^{+}

pump doesn’t just give

{Na}^{+}

and

K^{+}

a way to move down their electrochemical gradients. Instead, it actively transports

{Na}^{+}

and

K^{+}

against their electrochemical gradients.

The energy for this "uphill" movement comes from ATP hydrolysis (the splitting of ATP into ADP and inorganic phosphate). For every molecule of ATP that's broke down,

3

{Na}^{+}

ions are moved from the inside to the outside of the cell, and

2

K^{+}

ions are moved from the outside to the inside.

_Schemat zmodyfikowany na podstawie "The sodium-potassium exchange pump," przez Blausen staff (CC BY 3.0)._

Cykl pompy sodowo-potasowej

Źródło schematu: OpenStax Biology. Schemat zmodyfikowany przez Mariana Ruiz Villareal.

Pompa sodowo-potasowa transportuje sód (na zewnątrz komórki) i potas (do komórki) w powtarzającym się cyklu zmian konformacyjnych (kształtu). W każdym cyklu trzy jony sodu opuszczają komórkę, a dwa jony potasu do niej wnikają. Ten proces odbywa się w następujących krokach:

To begin, the pump is open to the inside of the cell. In this form, the pump binds readily to ${Na}^{+}$ ‍ ions (has a high affinity for them) and will take up three of them.
When the ${Na}^{+}$ ‍ ions bind, they trigger the pump to hydrolyze (break down) ATP. One phosphate group from ATP is attached to the pump, which is then said to be phosphorylated. ADP is released as a by-product.
Phosphorylation makes the pump change shape, re-orienting itself so it opens towards the extracellular space. In this conformation, the pump no longer binds readily to ${Na}^{+}$ ‍ ions (has a low affinity for them), so the three ${Na}^{+}$ ‍ ions are released outside the cell.
In its outward-facing form, the pump switches allegiances and now readily binds to (has a high affinity for) $K^{+}$ ‍ ions. It will bind two of them, and this triggers removal of the phosphate group attached to the pump in step 2.
Po odłączeniu grupy fosforanowej pompa powraca do swojej pierwotnej postaci, otwierając się w kierunku wnętrza komórki.
In its inward-facing shape, the pump no longer readily binds to $K^{+}$ ‍ ions, so the two $K^{+}$ ‍ ions will be released into the cytoplasm. The pump is now back to where it was in step 1, and the cycle can begin again.

This may seem complicated, but it actually just involves the protein going back and forth between two forms: an inward-facing form with high affinity for sodium (and low affinity for potassium) and an outward-facing form with high affinity for potassium (and low affinity for sodium). The protein can be toggled back and forth between these forms by the addition or removal of a phosphate group, which is in turn controlled by the binding of the ions to be transported.

The contents of this pop-up is a modified derivative of “Active transport,” by OpenStax College, Biology (CC BY 3.0). Download the original article for free at http://cnx.org/contents/185cbf87-c72e-48f5-b51e-f14f21b5eabd@9.85:25/Biology.

Because

3

{Na}^{+}

are exported for every

2

K^{+}

brought into the cell, the pump makes a small direct contribution to the resting membrane potential (making it slightly more negative than it would otherwise be). The pump's big contribution to the membrane potential, however, is indirect: It maintains steady

{Na}^{+}

and

K^{+}

gradients, which give rise to the membrane potential as

{Na}^{+}

and

K^{+}

move down their respective concentration gradients through leak channels.

The

{Na}^{+}

K^{+}

pump also plays a crucial role in maintaining the osmotic balance of the cell. Without the pump, intracellular osmolarity would exceed extracellular osmolarity at electrochemical equilibrium: Water would rush into the cell and the cell would burst!

From a pump-centric perspective, the resting membrane potential and the whole neuronal signaling apparatus can be viewed as a side effect of the cell’s attempt to avoid osmotic lysis.

Zmodyfikowany artykuł może być używany zgodnie z licencją CC BY-NC-SA 4.0.

Cytowane prace:

Purves, D., Augustine, G.J., Fitzpatrick, D., Katz, L.C., LaMantia, A.-S., McNamara, J.O., and Williams, S. M. (1997). Figure 2.3. Electrochemical equilibrium. In Neuroscience (2nd ed.). Sunderland, MA: Sinauer Associates. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK11054/figure/A134/?report=objectonly.

Bibliografia:

Electrochemical gradient. (2016, April 15). Retrieved April 23, 2016 from Wikipedia: https://en.wikipedia.org/wiki/Electrochemical_gradient.

Kandel, E.R., Schwartz, J.H., and Jessell, T.M. (1995). Nerve cells and behavior. In Essentials of neuroscience and behavior (pp. 31-35). Norwalk, CT: Appleton & Lange.

Kandel, E.R., Schwartz, J.H., and Jessell, T.M. (1995). Membrane potential. In Essentials of neuroscience and behavior (pp. 133-147). Norwalk, CT: Appleton & Lange.

Luigi Galvani. (2016, April 16). Retrieved April 23, 2016 from Wikipedia: https://en.wikipedia.org/wiki/Luigi_Galvani.

Nicholls, J.G., Martin, A.R., Wallace, B.G., and Fuchs, P.A. (2001). Ionic basis of the resting potential. In From neuron to brain (4th ed., pp. 77-90). Sunderland, MA: Sinauer Associates.

Nicholls, J.G., Martin, A.R., Wallace, B.G., and Fuchs, P.A. (2001). Signaling in nerve cells. In From neuron to brain (4th ed., pp. 9-15). Sunderland, MA: Sinauer Associates.

Openstax College, Biology. (2015, September 29). Nerve impulse transmission within a neuron. In OpenStax CNX. Retrieved from http://cnx.org/contents/GFy_h8cu@9.87:cs_Pb-GW@5/How-Neurons-Communicate.

Purves, D., Augustine, G.J., Fitzpatrick, D., Katz, L.C., LaMantia, A.-S., McNamara, J.O., and Williams, S. M. (1997). How ionic movements produce electrical signals. In Neuroscience (2nd ed.). Sunderland, MA: Sinauer Associates. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK11054/.

Purves, D., Augustine, G.J., Fitzpatrick, D., Katz, L.C., LaMantia, A.-S., and McNamara, J.O. (1997). Electrical signals of nerve cells. In Neuroscience (pp.37-50). Sunderland, MA: Sinauer Associates.

Reece, J. B., Urry, L. A., Cain, M. L., Wasserman, S. A., Minorsky, P. V., and Jackson, R. B. (2011). Ion pumps and ion channels establish the resting potential of a neuron. In Campbell biology (10th ed., pp. 1064-1066). San Francisco, CA: Pearson.

Sadava, D. E., Hillis, D.M., Heller, H.C., and Berenbaum, M.R. (2009). How do neurons generate and transmit electrical signals? In Life: The science of biology (9th ed., pp. 948-956). Sunderland, MA: Sinauer Associates.

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