Purpose of K+ channels in action potential

I understand that they serve to repolarize the neuron after the Na+ influx. What I don't understand is why this is important.

Meaning, let's say all the K+ channels disappeared. So now the potential is up near +50 mV about. It doesn't go back down quickly, because the K+ channels aren't there. Instead, we have to wait until the Na+/K+ pump can restore the proper intra-/extra- cellular balance between them. And then the neuron can fire again.

I can see that it will take longer for the potential to be restored. But don't we have to wait until the Na+ concentration is restored before we can fire again anyway? If we don't wait, wouldn't that interfere with maintaining sufficient/proper extracellular Na+ concentrations (which I would assume would have other effects)? And the same amount of time will be needed for the Na+ balance to be restored.

So what do we really gain by having a way to restore the charge differential?

Great question! However, your question is based on some misconceptions about what polarization means and how ion movement is involved, as well as the difference between equilibrium and the time it takes to get there. That's okay - it's a mistake that many many people learning about neurophysiology make, including instructors.

Na+/K+ concentrations actually change very very little during an action potential. The Na+/K+ pump establishes the concentration gradient, not the resting membrane potential. The resting membrane potential is caused by the concentration gradient plus the relative permeability of different ions via the Goldman equation: specifically, that permeability to K+ is much much higher than Na+.

When you open voltage-gated Na+ channels during an action potential, the relative permeability to sodium increases dramatically, so the new "equilibrium potential" is closer to the reversal potential for sodium (again, use the Goldman equation). There will be a net flow of ions (mostly Na+ coming in) until that new equilibrium potential is reached.

However, voltage-gated Na+ channels inactivate quickly, so that equilibrium isn't really reached. Instead, as the Na+ channels close, the new equilibrium potential is back near the original resting potential (for a third time, use the Goldman equation), because the primary permeability is to K+ through leak channels, and therefore the net current flow direction changes.

Okay, so what's the need for the voltage-gated potassium channels in all this? Well, the rising phase (sodium phase) of the action potential is fast because there is a really high conductance to Na+ so lots of Na+ can flow quickly in. In comparison, there is a lot less conductance of K+ through the leak channels. If all you have are leak channels, it takes a long time to return to rest. Equilibrium potential is just that: the equilibrium. It takes time to get to equilibrium. Voltage-gated K+ channels speed up that return to rest.

What if you had no K+ conductance, including no K+ leak channels? Well, then it doesn't matter at all what the relative concentration of K+ is inside and outside the cell: check the Goldman equation! You can't really have no conductance to anything at all, but if there is no dominant ion then the membrane potential will be something around zero. In that condition, the charge imbalance of the Na+/K+ pump process can contribute a couple mV, but nothing more than that.

All that said, to address your specific questions:

I understand that they serve to repolarize the neuron after the Na+ influx. What I don't understand is why this is important.

It's important for speed and for the minimum refractory period between action potentials. Nervous system activity would slow way way down if action potentials could only occur every 100 ms.

Instead, we have to wait until the Na+/K+ pump can restore the proper intra-/extra- cellular balance between them. And then the neuron can fire again.

But don't we have to wait until the Na+ concentration is restored before we can fire again anyway?

Na+/K+ pump is only needed to maintain ion balance over a very long term. On the time course of a single action potential, the concentrations of Na+ and K+ do not change appreciably. That's not what repolarization is.

So what do we really gain by having a way to restore the charge differential?


You can also see my answers on some related questions:

Why is it possible to calculate the equilibrium potential of an ion using the Nernst equation from empirical measurements in the cell at rest?

Why does K+ moves out of the cell?


Certain cells in the body are electrically active and can relay and sustain voltage fluctuations. These voltage fluctuations allow the propagation of signals and can be thought of as a means of communication between the cells. How these fluctuations come about is to a large extent dependent upon the cell membrane and the movement of ions across it.


The cell membrane consists of a lipid bilayer structure that usually does not allow electrical ions to pass through freely. Therefore, there is a difference in ion concentration maintained across the cell membrane, causing it to be polarized. The maintenance of a potential across the cell membrane is called ‘membrane potential’. Usually, the inside of the cell is more negative than the outside, and the membrane potential is typically at -70 mV (millivolts). This is also described as the state of a normal resting membrane potential.

The membrane structure also harbors certain ion transporters that support the membrane potential. For example, potassium leak channels cause the escape of potassium ions from inside the cells. This is also supported by the fact that the intracellular fluid contains a high concentration of potassium ions compared to the extracellular environment, which consists of high concentrations of sodium and chloride ions. The high intracellular concentration of potassium creates a gradient for the efflux of potassium ions through the leaky channels, resulting in the formation of the negative resting membrane potential. The Na+/K+ ATPase pump, in response, helps to maintain the concentration gradient.

Similarly, there are other channels embedded within the cell membrane which are responsible for the generation of an ‘action potential’

But what causes the action potential? From an electrical aspect, it is caused by a stimulus with certain value expressed in millivolts [mV]. Not all stimuli can cause an action potential. Adequate stimulus must have a sufficient electrocal value which will reduce the negativity of the nerve cell to the threshold of the action potential. In this manner, there are subthreshold, threshold, and suprathreshold stimuli. Subthreshold stimuli cannot cause an action potential. Threshold stimuli are of enough energy or potential to produce an action potential (nerve impulse). Suprathreshold stimuli also produce an action potential, but their strength is higher than the threshold stimuli.

So, an action potential is generated when a stimulus changes the membrane potential to the values of threshold potential. The threshold potential is usually around -50 to -55 mV. It is important to know that the action potential behaves upon the all-or-none law. This means that any subthreshold stimulus will cause nothing, while threshold and suprathreshold stimuli produce a full response of the excitable cell.

Is an action potential different depending on whether it’s caused by threshold or suprathreshold potential? The answer is no. The length and amplitude of an action potential are always the same. However, increasing the stimulus strength causes an increase in the frequency of an action potential. An action potential propagates along the nerve fiber without decreasing or weakening of amplitude and length. In addition, after one action potential is generated, neurons become refractory to stimuli for a certain period of time in which they cannot generate another action potential.

Andersen-Tawil Syndrome

Molecular Correlate of IK1

The inward rectifier potassium current IK1 is the major determinant of the resting membrane potential in the heart and participates in the most terminal phase of action potential repolarization. 4 IK1 is conducted by homo- and/or heterotetrameric channels formed by coassembly of the Kir2.x subfamily of proteins (Kir2.1, Kir2.2, and Kir2.3). Message and protein expression studies indicate that Kir2.1 is the most abundant subfamily member in ventricular tissue. 17,18 The finding that mutations in KNCJ2 cause human disease (but not in the genes encoding Kir2.2 and 2.3) further underscores the pivotal role of Kir2.1 as a primary component of IK1.

Phases of action potential & role of gated ion channels

1. All cells have a membrane potential however, only certain kinds of cells, including neurons and muscle cells, have the ability to generate changes in their membrane potentials. Collectively these cells are called excitable cells. The membrane potential of an excitable cell in a resting (unexcited) state is called the resting potential, and a change in the resting potential may result in an active electrical impulse.

2 Neurons have special ion channels, called the gated ion channels, that

ahoy the cell to change its membrane potential in response to stimuli the cell receives. If the stimulus opens a potassium channel, an increase in efflux of potassium will occur, and the membrane potential will become more negative. Such an increase in the electrical gradient across the membrane is called a hyperpolarization. If the channel opened by the stimulus is a sodium channel, an increased influx of sodium will occur, and the membrane potential will become .less negative. Such a reduction in the electrical gradient is called a depolarization. Voltage changes produced by stimulation of this type are called graded potentials because the magnitude of change (either hyperpolarization or depolarization) depends on the strength of the stimulus: A larger stimuls will open more channels and will produce a larger change in permeability.

  1. In an excitable cell, such as a neuron, the response to a depolarizing
    stimulus is graded with stimulus intensity only up to, a particular level of depolarization, called the threshold potential. If a depolarization reaches the threshold, a different type of response, called an action potential, will be triggered.
  2. The action potential is the nerve impulse. It is a nongraded all-or-none event, meaning that the magnitude of the action potential is independent of the strength of the depolarizing stimulus that produced it, provided the depolarization is sufficiently large to reach threshold. Once an action potential is triggered, the membrane potential goes through a stereotypical sequence of changes.
  3. During the depolarizing phase, the membrane polarity briefly reverses, with the interior of the cell becoming positive with respect to the outside. This is followed rapidly by a steep repolarizing phase, during which the membrane potential returns to its resting level. Fig. 2.5.
  4. There may also be a phase, called the undershoot, during which the membrane potential is more negative than the normal resting potential. The whole event is typically over within a few milliseconds.

Role of gated ion channelgein the action potential:

The action potential arises because the plasma membranes of excitable cells have special voltage-gated channels. These ion channels have gates that open and close in response to changes in membrane potential. Fig. 2.4, 2.5

Two types of voltage-gated channels contribute to the action potential: potassium channels and sodium channels.

Each potassium channel has , a single gate that is voltage-sensitive it is closed when resting and opens slowly in response to depolarization.

By contrast, each sodium channel has two voltage-sensitive gates

(i) an ‘activation gate, that is closed when resting and responds to depolarization by opening rapidly, and

(ii) an inactivation gate, that is open when resting and responds to depolarization by closing slowly.

In the membrane’s resting state, the inactivation gate is open but the activation gate is closed, so the channel does not allow Na + to enter the neuron. Upon

depolarization the activation gate opens quickly, causing an influx of Na, which depolarizes the membrane further, opening more voltage-gated sodium channels and causing still more depolarization. This inherently explosive process. example of positive feed back, continues until all the sodium channels at the stimulated site of the membrane are open.

Two factors underlie the rapid repolarizing phase of the action potential as membrane potential is returned to rest. First, the sodium channel inactivation gate, which is slow to respond to changes in voltage, has time to respond to depolarization by closing, returning sodium permeability to its low resting level. Second, potassium channels whose voltage-sensitive gates respond relatively slowly to depolarization, have had time to open. As a result, during repolarization, K + flows rapidly out of the cell, helping restore the internal negativity of the resting neuron. The potassium channel gates are also the main cause of the undershoot, or hyperpolarization, which follows the repolarizing phase. Instead of returning immediately to their resting position, these relatively slow-moving gates remain open during the undershoot, allowing potassium to keep flowing out of the neuron. The continued potassium outflow makes the membrane potential more negative. During the undershoot, both the activation gate and the inactivation gate of the sodium channel are closed. If a second depolarizing stimulus arrives during this period, it will be unable to trigger an action potential because the inacthiation gates have not had time to reopen after the preceding action potential. This period when the neuron is insensitive to depolarization is called the refractory period, and it sets the limit on the maximum rates at which action potentials can be generated. Fig. 2.6

Electrically Active Cell Membranes

Most cells in the body make use of charged particles, ions, to build up a charge across the cell membrane. Previously, this was shown to be a part of how muscle cells work. For skeletal muscles to contract, based on excitation–contraction coupling, requires input from a neuron. Both of the cells make use of the cell membrane to regulate ion movement between the extracellular fluid and cytosol.

As you learned in the chapter on cells, the cell membrane is primarily responsible for regulating what can cross the membrane and what stays on only one side. The cell membrane is a phospholipid bilayer, so only substances that can pass directly through the hydrophobic core can diffuse through unaided. Charged particles, which are hydrophilic by definition, cannot pass through the cell membrane without assistance (Figure 1). Transmembrane proteins, specifically channel proteins, make this possible. Several channels, as well as specialized energy dependent “ion-pumps,” are necessary to generate a transmembrane potential and to generate an action potential. Of special interest is the carrier protein referred to as the sodium/potassium pump that moves sodium ions (Na + ) out of a cell and potassium ions (K + ) into a cell, thus regulating ion concentration on both sides of the cell membrane.

Figure 1. Cell Membrane and Transmembrane Proteins The cell membrane is composed of a phospholipid bilayer and has many transmembrane proteins, including different types of channel proteins that serve as ion channels.

The sodium/potassium pump requires energy in the form of adenosine triphosphate (ATP), so it is also referred to as an ATPase. As was explained in the cell chapter, the concentration of Na + is higher outside the cell than inside, and the concentration of K + is higher inside the cell is higher than outside. That means that this pump is moving the ions against the concentration gradients for sodium and potassium, which is why it requires energy. In fact, the pump basically maintains those concentration gradients.

Ion channels are pores that allow specific charged particles to cross the membrane in response to an existing concentration gradient. Proteins are capable of spanning the cell membrane, including its hydrophobic core, and can interact with the charge of ions because of the varied properties of amino acids found within specific domains or regions of the protein channel. Hydrophobic amino acids are found in the domains that are apposed to the hydrocarbon tails of the phospholipids. Hydrophilic amino acids are exposed to the fluid environments of the extracellular fluid and cytosol. Additionally, the ions will interact with the hydrophilic amino acids, which will be selective for the charge of the ion. Channels for cations (positive ions) will have negatively charged side chains in the pore. Channels for anions (negative ions) will have positively charged side chains in the pore. This is called electrochemical exclusion, meaning that the channel pore is charge-specific.

Ions can also be specified by the diameter of the pore. The distance between the amino acids will be specific for the diameter of the ion when it dissociates from the water molecules surrounding it. Because of the surrounding water molecules, larger pores are not ideal for smaller ions because the water molecules will interact, by hydrogen bonds, more readily than the amino acid side chains. This is called size exclusion. Some ion channels are selective for charge but not necessarily for size, and thus are called a nonspecific channel. These nonspecific channels allow cations—particularly Na + , K + , and Ca 2+ —to cross the membrane, but exclude anions.

Ion channels do not always freely allow ions to diffuse across the membrane. They are opened by certain events, meaning the channels are gated. So another way that channels can be categorized is on the basis of how they are gated. Although these classes of ion channels are found primarily in cells of nervous or muscular tissue, they also can be found in cells of epithelial and connective tissues.

A ligand-gated channel opens because a signaling molecule, a ligand, binds to the extracellular region of the channel. This type of channel is also known as an ionotropic receptor because when the ligand, known as a neurotransmitter in the nervous system, binds to the protein, ions cross the membrane changing its charge (Figure 2).

Figure 2. Ligand-Gated Channels When the ligand, in this case the neurotransmitter acetylcholine, binds to a specific location on the extracellular surface of the channel protein, the pore opens to allow select ions through. The ions, in this case, are cations of sodium, calcium, and potassium.

A mechanically gated channel opens because of a physical distortion of the cell membrane. Many channels associated with the sense of touch (somatosensation) are mechanically gated. For example, as pressure is applied to the skin, these channels open and allow ions to enter the cell. Similar to this type of channel would be the channel that opens on the basis of temperature changes, as in testing the water in the shower (Figure 3).

Figure 3. Mechanically Gated Channels When a mechanical change occurs in the surrounding tissue, such as pressure or touch, the channel is physically opened. Thermoreceptors work on a similar principle. When the local tissue temperature changes, the protein reacts by physically opening the channel.

A voltage-gated channel is a channel that responds to changes in the electrical properties of the membrane in which it is embedded. Normally, the inner portion of the membrane is at a negative voltage. When that voltage becomes less negative, the channel begins to allow ions to cross the membrane (Figure 4).

Figure 4. Voltage-Gated Channels Voltage-gated channels open when the transmembrane voltage changes around them. Amino acids in the structure of the protein are sensitive to charge and cause the pore to open to the selected ion.

A leakage channel is randomly gated, meaning that it opens and closes at random, hence the reference to leaking. There is no actual event that opens the channel instead, it has an intrinsic rate of switching between the open and closed states. Leakage channels contribute to the resting transmembrane voltage of the excitable membrane (Figure 5).

Figure 5. Leakage Channels In certain situations, ions need to move across the membrane randomly. The particular electrical properties of certain cells are modified by the presence of this type of channel.

Action potentials

Figure 21-2. Lodish 4th edition (a) An action potential is a sudden, transient depolarization of the membrane followed by repolarization to the resting potential of about -60 mV. This recording of the axonal membrane potential in a presynaptic neuron shows that it is generating one action potential about every 4 milliseconds. (b) The membrane potential across the plasma membrane of a presynaptic neuron is measured by a small electrode inserted into it. Action potentials move down the axon at speeds up to 100 meters per second. Their arrival at a synapse causes release of neurotransmitters that bind to receptors in the postsynaptic cell, generally depolarizing the membrane (making the potential less negative) and tending to induce an action potential in it.

The Channels of an Action Potential

Action potentials in neurons are mostly based on the voltage-gated Na+ channel, some neurons use both the voltage-gated Na+ channel and a voltage-gated K+ channel, some neurons use only the voltage-gated Na+ channel and some neurons use the voltage-gated Ca+2 channel

We will use the classic example of an action potential from the giant axon of the squid (invertebrate), also the action potential found in non-myelinated axons of mammals. This action potential has two components: voltage-gated Na+ channels and voltage-gated K+ channels

Voltage gated Na+ channel:
The channel has three states, closed, open and inactive.
Closed to Open: Depolarization is necessary to open the channel and therefore it acts to activate itself in a regenerative cycle. More Na+ influx depolarizes the membrane which opens more channels which depolarizes the membrane more.
Open to Inactive: Depolarization is also necessary to inactive the channel. Once the channel is open it will then also switch to the inactive state and can not be opened again
Inactive to closed: The channel will not switch back to the closed state until the membrane has repolarized (i.e. gone back towards the original resting membrane potential. Once in the closed state it can then be reopened

Voltage-gated K+ channel (called the delayed rectifying K+ channel)
This channel has only two states, closed and open.
Closed to open: The channel is opened with a strong depolarization, the type you would normally get in an action potential. This channel works to bring the membrane back towards the Nernst potential for K+ i.e. hyperpolarize the membrane
Open to closed: The channel will close when the membrane becomes hyperpolarized or repolarized. Therefore this channel works to shut itself down.

The components of an action potential

Figure 7-32 Lodish 5th edition. Depolarization of the plasma membrane due to opening of gated Na+ channels. (a) Resting neurons non gated K+ channels are open, but the more numerous gated Na+ channels are closed. The movement of K+ ions outward establishes the inside-negative membrane potential characteristic of most cells. (b) Opening of gated Na+ channels permits an influx of sufficient Na+ ions to cause a reversal of the membrane potential.


- level of depolarization needed to trigger an action potential (most neurons have a threshold at -50 mV (i.e. 10 to 15 mV depolarization)
- an action potential is an all or none event, if a nerve is at rest the amplitude on one action potential will be the same all along the nerve independent of the stimulus strength.
- threshold reflects the need to trigger the opening of the voltage-gated sodium channel (need a depolarization of about 10 to 15 mV to open)

Action potential rising phase

- as sodium channels open, Na+ ions flow into cell, depolarizes the cell more and more sodium channels open = a regenerative response - regenerative opening of sodium channels drives the membrane potential towards a peak of the Nernst equilibrium potential for Na+

Peak of Action Potential

- during an action potential the membrane potential goes towards the Nernst equilibrium potential for Na+
- in terms of Goldman-Katz equation now permeability to Na+ is dominant (K+ and Cl- minor components) therefore membrane potential goes towards ENa
- usually falls short of ENa, less driving force on Na+ and the channels begin to inactivate rapidly after activation

Falling Phase of Action Potential

- after reaches peak now action potential falls, membrane potential falls back towards rest
- why? Why doesn't the action potential stay around ENa?
- two reasons:
i) Na+ channels move into an inactive state
ii) delayed K+ channels open (giant axon of squid or non-myelinated axons of vertebrates)

1) Inactivating Na+ channels -
- Na+ channels go to an inactivated state after 1-2 msec after first opening
- inactivated = can NOT be reopened
- therefore the membrane potential now determined mostly by K+ (same as for resting potential) and membrane starts to repolarize

2) Delayed K+ channels open (called delayed rectifier voltage-gated like Na+ channel)
- open after about 1-2 msec of threshold depolarization
- now K+ flows out of the cell and speeds the repolarization process
- cause the hyperpolarization after the action potential because open K+ channels make the K+ permeability higher than at rest and membrane more negative on inside

-hyperpolarization of membrane causes K+ channels to close
-then membrane settles back to rest


- voltage-gated Na+ channels and voltage-gated K+ channels now closed so the membrane goes back to the resting state
- i.e. the leak channels are the only channels open and again set the membrane potential

Refractory period

-divided into two parts
i) absolute refractory period
ii) relative refractory period

1) Absolute refractory period
- Na+ channels are inactive and CAN NOT be opened no matter how much the membrane is depolarized at this time
- another action potential can not be generated in this part of the nerve at this time

2) Relative refractory period
- as membrane repolarize's = goes to more negative potentials this triggers the Na+ channels to move from an inactive state to a close state.
- hyperpolarization by the opening of the K+ channels helps this process
- once Na+ channel is in the closed state can be opened again with depolarization
- during relative refractory period, more and more Na+ channels available to be opened and therefore increase the chances of firing an action potential

Frequency of Action Potentials

- If the action potential if all or none how does a nerve convey the strength of a stimulus?
- e.g. how does a sensory nerve distinguish between a light touch (feather) and a rough abrasive touch (sand paper)?
- the information is indicted by the frequency of the action potentials along the nerve.
-the stimulus strength (current input in to the nerve either experimentally by injecting a large current or in real life by response of touch receptor) triggers different frequency of action potentials

-therefore: light touch - infrequent action potentials rough touch - more frequent action potentials
- the refractory period limits the frequency of the action potential
- during the relative refractory period an action potential can be generated but with an increased threshold and a reduced amplitude
- increased threshold because have to over come hyperpolarization
- decrease amplitude because less Na+ channels are available to open (many are still in the inactive state) and so get less Na+ flowing into the cell
(in other words the permeability or conductance of Na+ is reduced during relative refractory period - increases towards the end of the period)

Direction of Action Potentials

Figure 21-14, Lodish 4th edition OR Figure 7-35, Lodish 5th edition. Unidirectional conduction of an action potential due to transient inactivation of voltage-gated Na+ channels. At time 0, an action potential (purple) is at the 2-mm position on the axon. The membrane depolarization spreads passively in both directions along the axon (Figure 21-11). Because the Na+ channels at the 1-mm position are still inactivated (green), they cannot yet be reopened by the small depolarization caused by passive spread. Each region of the membrane is refractory (inactive) for a few milliseconds after an action potential has passed. Thus, the depolarization at the 2-mm site at time 0 triggers action potentials downstream only at 1 ms an action potential is passing the 3-mm position, and at 2 ms, an action potential is passing the 4-mm position.

- the refractory period also sets the direction of an action potential
- depolarizing current from the action potential can spread passively in either direction
- one way the Na+ channels are in a closed state and are ready to be opened, therefore the spreading current can trigger an action potential in this neighbouring region
- the other way the Na+ channels are in an inactive state and can not be opened therefore the spreading current has no effect on the channels in this region and an action potential is not trigger

Channels and receptors

Throughout the lectures we will be introducing a wide range of ion channels. These range from leak channels (K+, Na+, Cl- etc.), voltage-gated ion channels (K+, Na+ and Ca+2 etc.) and aligned gated ion channels (K+/Na+, Cl- etc.).

Most of the proteins that make up the different types of ion channels are very similar in their structure and have conserved amino acid sequences. This degree of conservation occurs between different types of channels and across species. So for instance the Drosophila voltage-gated Na+ channel is very similar to the human voltage-gated Na+ channel etc. All the ion channels are composed of alpha helices that span the lipid bilayer. Those that contact the lipid bilayer are composed of hydrophobic amino acids (Phe, Ile, Leu etc.) that span about 20 amino acids. Those alpha helices that line the pore are composed of hydrophilic residues to allow ion flow (Lys, Arg etc.).

Channel pore

All the ion channels in question have a common feature. A pore that allows the ion(s) in question to flow across the lipid bilayer. The pore is specific to a certain ion or ions. For instance the leak K+ channel only allows K+ ions to flow across the membrane.

Figure 7-16, Lodish 5th edition. Mechanism of ion selectivity and transport in resting K+ channels. (a) Schematic diagram of K+ and Na+ ions hydrated in solution and in the pore of a K+ channel. (b) High-resolution electron-density map obtained from x-ray crystallography showing K+ ions passing through the selectivity filter.


The voltage sensor is an alpha helix is found in the channel and spans the membrane. The voltage-sensor has positive charges at every third amino acid. The sensor moves in response to depolarization (i.e. the increase positive charge on the interior membrane causes the physical movement of the voltage-sensor). The sensor alpha helix is buried within the channel protein (i.e. protected from hydrophobic lipid bilayer by the rest of the ion channel protein).

The voltage-sensors move in response to depolarization to open the ion channel. One model of how the voltage-sensor works is based on a twist or spiral movement that cause the alpha helix to move within the membrane. Experimenters can measure this movement of the voltage-sensory but you'll have to wait until Biology 455 to learn all about that.
The following is a movie of one model of how the voltage-sensor moves. (WARNING: a big file!!).
Movie of moving voltage-sensor

Volume 2

Lee P. Haynes , Robert D. Burgoyne , in Handbook of Cell Signaling (Second Edition) , 2010

Class E: KChIPs

K + Channel Interacting Proteins (KChIPs) [62, 63] regulate A-type K + channels currents and the traffic of these channels to the plasma membrane. KChIP1 is the only member of the KChIP subfamily that is myristoylated. Modulation of Kv4.2 K + channels in CHO cells and Kv4.2 and Kv4.3 K + channels in Xenopus oocytes via arachidonic acid has been shown to be dependent on KChIP1 [64] . KChIP2 also regulates Kv4.2 and Kv4.3 K + channels, and KChIP2 knockout mice are highly susceptible to ventricular tachycardia due to the loss of a transient outward K + channel current in the heart [65] . KChIP3 is the same protein as calsenilin, which interacts with presenilin-1 and 2. Presenilin-1 mutations are the most common cause of familial Alzheimer’s disease, and calsenilin interacts with the endogenous 20-kDa C-terminal fragment of presenilin 2 that is a product of regulated proteolytic cleavage [66] . KChIP3/calsenilin is also the same protein as Downstream Regulatory Element Antagonist Modulator (DREAM), which is a Ca 2+ -regulated transcriptional repressor involved in pain modulation [67,68] . An alternative splice variant of KChIP4 (KChIP4a) encodes a protein with a novel N-terminus called the KIS (K-channel inactivation suppressor) domain. The KIS domain appears to be important for the abolishment of fast inactivation of Kv4.3 channels [69] . KChIPs are essential in controlling the biochemical properties and trafficking of Kv4 family channels [70] , and cell surface expression of these channels may proceed though a novel post-endoplasmic reticulum vesicular transport pathway, as observed for the traffic of Kv4.2 by KChIP1 in mammalian cells [71, 72] .

Resting and action potential

I&rsquom confused about the permanently opened sodium or potassium ion channel.

Correct me if I&rsquom wrong:
Both sodium and potassium ions move through the axon membrane through sodium and potassium ion voltage-gated channels and sodium-potassium pump.
Some of these voltage-gated channels are permanently opened so the ions can move in and out of axon freely through them. Others gated channels only open or close due to a change in voltage across the axon membrane.

&bullQuestion: Do these permanently opened gated channels open at all times? that means at any time, during resting or action potential, these channels always open? If this is true, does it mean that there is always sodium or potassium ions moving in or out of axon? Thus, resting or action potential is only formed because of the others openable channel causing more of an ion to move in or out of axon?

Not what you're looking for? Try&hellip

Voltage-gated channels, as their name implies, are gated by voltage, meaning that they open and close in response to voltage changes.
In addition to these there exist some other channels (generally K+ channels) that are 'leaky', i.e. constitutive open and not gated. Which dissipates some of the concentration gradient.

Yes, this is absolutely correct. The reason this difference in number of channels open (many more K + ones open than Na+ ones) leads to the build-up of the resting potential is that IN ALL CELLS [including neurons], the intracellular K+ is high, and the extracellular Na+ is high (e.g. normal plasma [=extracellular] K+ = 3.5-5.0 mM/l plasma Na+ = 135-150 mM/l, [at least at the hospital I trained at]) (and this difference is maintained by Na+-K+-ATPase (sodium-potassium pump)), is that this difference in ionic concentrations of K+ and Na+ (=concentration gradients) is what drives movement of ionsTHROUGH THE VERY FEW Na+ BUT MANY MORE K+ open channels.

The negative intracellular potential is also contributed to by the fact that the Na+, K+ - ATPase is not an equimolecular pump, but rather exchanges 3 Na+ ions in one direction [here outwards] for 2 K+ ions i the opposite direction [here inwards], so that the pump alone tends to build up negativity intracellularly. This action of the sodium-potassium pump also comes in useful in the intestine for absorption of digested food material and in the renal proximal tubule cells for reabsorption (both examples of active transport).

Since OP seems to have a quite keen eye for detail, perhaps you would be kind enough to explain hereupon the Nernst Equation [too mathematical for me!], and the difference of its application to Cl- and K+ on the one hand against its application to Na+ on the other.

(Original post by macpatelgh)
Yes, this is absolutely correct. The reason this difference in number of channels open (many more K + ones open than Na+ ones) leads to the build-up of the resting potential is that IN ALL CELLS [including neurons], the intracellular K+ is high, and the extracellular Na+ is high (e.g. normal plasma [=extracellular] K+ = 3.5-5.0 mM/l plasma Na+ = 135-150 mM/l, [at least at the hospital I trained at]) (and this difference is maintained by Na+-K+-ATPase (sodium-potassium pump)), is that this difference in ionic concentrations of K+ and Na+ (=concentration gradients) is what drives movement of ionsTHROUGH THE VERY FEW Na+ BUT MANY MORE K+ open channels.

The negative intracellular potential is also contributed to by the fact that the Na+, K+ - ATPase is not an equimolecular pump, but rather exchanges 3 Na+ ions in one direction [here outwards] for 2 K+ ions i the opposite direction [here inwards], so that the pump alone tends to build up negativity intracellularly. This action of the sodium-potassium pump also comes in useful in the intestine for absorption of digested food material and in the renal proximal tubule cells for reabsorption (both examples of active transport).

Action Potentials

In response to the appropriate stimulus, the cell membrane of a nerve cell goes through a sequence of depolarization from its rest state followed by repolarization to that rest state. In the sequence, it actually reverses its normal polarity for a brief period before reestablishing the rest potential.

The above example of the squid action potential was patterned after a measured action potential shown in West's Medical Physics. The approximate time intervals shown were scaled from time markers on the experimental trace.

The action potential sequence is essential for neural communication. The simplest action in response to thought requires many such action potentials for its communication and performance. For modeling the action potential for a human nerve cell, a nominal rest potential of -70 mV will be used. The process involves several steps:

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The following discussion is an attempt to characterize the successive steps involved in the production of an action potential typical of mammalian nerve cells.

Action potential

An action potential is a message in the form of an electrical impulse caused by a rapid change in a cell's membrane potential.

When a stimulus reaches the threshold at the axon hillock, an action potential is generated.

An action potential relies on many protein channels. In a neurone, the Potassium leak channel and Sodium-Potassium pump maintain the resting potential. The voltage gated sodium channels and the voltage gated potassium channels are involved in the progression of an action potential along the membrane.

The action potential progression can be separated into several steps

  1. Voltage channels are closed and the Potassium (K + ) leak channel and the sodium (Na + ) pump maintain the resting membrane potential of -70 mV. The Sodium/Potassium Pump (ATPase) is responsible for maintaining the membrane potential at -70mv, the protein actively pumps three sodium ions out of the cell and pumps two potassium ions into the cell.
  2. The neurone becomes stimulated. The voltage gated sodium channels begin to open and the membrane potential begins to slowly depolarises and sodium enters the cell down its concentration gradient. All the voltage-gated Sodium channels open when the membrane potential reaches around -55 mV and there's a large influx of Sodium, causing a sharp rise in voltage. As the potential nears +30mV, the rate of depolarisation slows down as the voltage-gated Sodium channels become saturated and inactivate, preventing further sodium ions from entering the cell. open, and potassium leaves the cell down its concentration gradient. The depolarization of the cell stops and repolarisation can occur through these voltage-gated Potassium channels.
  3. Voltage gated sodium channels are completely deactivated and potassium floods out through the voltage gated potassium channels,
  4. Voltage gated potassium channels are slow to close, and therefore hyperpolarisation occurs. This is where the membrane potential drops below the resting potential of -70 mV as potassium continues to leave.
  5. Once the voltage gated potassium channels close, the resting state can be re-established through the Potassium leak channel and Sodium pump.

The action potential travels along the neurone's axon via current loops in order to reach the axon terminal.

An action potential is a transient, electrical signal, which is caused by a rapid change in resting membrane potential (-70 mV). This occurs when the threshold potential (-55 mV) is reached, this causes a rapid opening in the voltage-gated sodium channels leading to an influx of sodium ions into the cell. The threshold potential also causes a slow opening of voltage-gated potassium channels leading to the efflux of potassium ions out of the cell. This causes the cell to depolarise, meaning the inside of the cell is now more positive compared to the outside.

The action potential starts in the axon hillock as there is a high density of voltage-gated sodium channels here, it is also where graded potentials need to reach the threshold potential to cause an action potential. If the graded potential do not reach the supratheshold level, then an action potential is not triggered and the graded potential is known as subthreshold [1] . Above the threshold, increase in the strength of a stimulus will not increase the size or the amplitude of the corresponding action potential. The strength of a stimulus, or the size of a graded potential, is indicated by the frequency of action potentials travelling along a neurone.

The action potential travels via current loops. In myelinated axons its jumps from node of ranvier to Node of Ranvier, this is a process known as saltatory conduction.

There are two main factors which affect the conduction velocity: the myelination of the axon and the axon diameter. As myelin sheath acts as an electrical insulator, the current cannot pass through the myelinated areas and will have to jump from node to node (saltatory conduction). When the diameter of the axon is increased, there is more room for local current flow, therefore, the internal membrane resistance decreases, and in turn, increases the conduction velocity.

An example of myelination-related disease is Multiple Sclerosis, which causes the immune system to attack the myelin sheath, resulting in demyelination of the axon. When the axon is demyelinated, the conduction velocity will drastically decrease, therefore, the action potential travels slower to the effector (e.g. muscle), leading to the loss of movement.

The point at which the membrane of an axon is depolarised causes a local circuit to be set up between the depolarized region and the region either side of it. This also causes the resting at regions either side to become depolarized. In this way, the action potential sweeps along the axon.

The refractory period prevents the action potential from travelling backwards. There are two types of refractory periods, the absolute refractory period and the relative refractory period. The absolute refractory period is when the membrane cannot generate another action potential, no matter how large the stimulus is. This is because the voltage-gated sodium ion channels are inactivated. The relative refractory period is when the membrane can produce another action potential, if the stimulus is larger than normal. This is because some of the voltage-gated sodium ion channels have recovered and the voltage-gated potassium ion channels are still open. The relative refractory period is the period of hyperpolarization after an action potential [2] .

Action potentials in neurons are also known as "nerve impulses" or "spikes" [3] [4] .