Repolarization

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Repolarization

Introduction

Repolarization is the phase that follows depolarization. During an action potential, the first stage is depolarization in which sodium ion channels open causing an influx of sodium ions into the neuron. This causes the membrane potential to reach approximately +40mV from a resting membrane potential of -70mV. At this membrane potential of about +40mV, sodium ion channels begin to close, and voltage gated potassium ion channels start to open. There is then a potassium ion efflux through these potassium ion channels leaving the cell. This efflux causes the membrane potential to drop back down to a membrane potential of 0mV as the membrane potential becomes more negative. 

Action_Potential

This repolarization continues to drop below 0mV and the membrane potential becomes more negative until it reaches its resting membrane potential of -70mV. The membrane is now in a phase of hyperpolarization. 

After reaching its resting membrane potential there is a brief overshoot to approximately -75mV, following this overshoot these voltage gated potassium ion channels close and membrane potential returns to -70mV. The reason for this slightly lower resting membrane potential of about -75mV as opposed to the original resting membrane potential of -70mV is due to the slow inactivation of voltage gated potassium ion delayed rectifier channels. 

This resting membrane potential is maintained by a sodium/potassium ion pump. For each ATP molecule broken down, 3 sodium ions are pumped out and 2 potassium ions move into the cell ensuring a net negative potential inside the cell. Asides from these voltage gated potassium ion channels, A-type channels and Calcium ion activated potassium ion channels are also some of the key channels associated with repolarization.

Calcium-activated potassium channel

Voltage gated Potassium ion channel

As implied by the name, voltage gated potassium ion channels are transmembrane channels which allow potassium ions to pass through. They are sensitive to voltage changes in the membrane potential of the cell as also implied by the name. This selectivity filter is found at the narrowest part of the transmembrane pore. 

Structure

These channels are tetramers of four identical subunits arranged in a ring structure. Each subunit contains 6 hydrophobic alpha-helical subunits that are membrane spanning. A voltage sensor is found is S4. Amino and carboxyl termini are found on the intracellular side. These channels consist of alpha subunits. These alpha subunits form the conductance pore. These alpha subunits can classify into 12 classes namely Kvα1-12. Similarly, these channels consist of beta subunits. These are auxillary proteins. These subunits associate with alpha subunits and they modulate the activity of the voltage gated potassium ion channels. Certain parts of the subunits are found to play a part in selectivity to potassium ions. The Thr-Val-Gly-Tyr-Gly amino acid sequence is important in potassium ion selectivity. On passing through the channel, the potassium ions interact with atomic components of the Thr-Val-Gly-Tyr-Gly amino acid sequences, it does not react with water molecules. 

Ion Transport

Although sodium ions are smaller than potassium ions, they are unable to pass through the voltage gated channel. The reason for this is that both sodium and potassium ions are solvated by water molecules in the aqueous environment before passing through the voltage gated potassium ion channel. On passing through the channel, the potassium ions end their interactions with water molecules and form interactions with carbonyl groups found in the transmembrane channel.

The selectivity filter diameter is too large for sodium ions and the right size for potassium ions.  The distance between carbonyl groups is too great to solvate sodium ions but is able to adequately allow and bind to potassium ions.

Conformations (open and closed)

In order to understand the reason behind its voltage change responses, it is essential to take a look at its structure. Conformational changes in the voltage sensor domains cause a transfer of 12-13 charges across the electric field of the membrane. Four charge residues move across the transmembrane field contributing the gating charge. These four arginine residues are located at every third position on the S4 segment. Certain parts of these channel subunits are responsible for the open and closed confirmations. 

Initially the channel opens on the membrane potential becoming positive. The voltage sensing domain of this type of gating consists of 6-7 positive charges. The membrane potential changes here move the alpha helix into the lipid bilayer. Following this movement, there is a conformational change in the S5-S6 helices forming the channel pore. This will hence cause the pore to open or close. 

The next conformation is called the N-type inactivation. In the N-type inactivation, the voltage gated potassium ion channels after opening will enter a closed conformation state. This is distinct for the fact that the channel will not open even if the specific transmembrane voltage needed to open them is achieved. N-type inactivation is mediated by the amino terminal domains of potassium ion channels or auxiliary proteins. This type of inactivation is called as the ball and chain model. In the ball and chain model, the ball is formed by the protein’s N-terminus, this N-terminus ball is tethered through the loop to the remaining parts of the protein. This loop is said to be the chain. Ions are blocked from passing through the pore by the tethered ball. 

There are several methods by which voltage gated potassium ion channels can be blocked, this will hence block repolarization. Tetraethylammonium is one such antagonist which is a very effective antagonist in voltage gated potassium ion channels. Similarly, Dendrotoxins block these channels .When voltage gated potassium ion channels are blocked, there is no repolarization, and the cell voltage will not drop. The sodium channel de-inactivation is slowed so much so that the sodium ion current is not sufficient enough to depolarize and continue firing. 

Types of potassium ion channels

There are 4 types of potassium ion channels involved in repolarization. These are Kv1, Kv2, Kv3 and Kv4. 

Kv1

Repolarization of the axon is achieved by the Kv1 channel. 

Kv2

Activation of the Kv2 channel is achieved more slowly in contrast to the Kv4 channels which are activated much more rapidly. 

Kv3

The Kv3 channel opens when the membrane potential is more positive, it also deactivates at a much faster rate than the other channels. Certain parts of the brain such as the basal ganglia, hippocampus and brain stem have a very large number of Kv3 channels. These areas have very short duration action potentials lasting microseconds and hence have quick repolarization. 

Kv4

After depolarization of a neuron, Kv4 channels are the channels responsible for primary repolarization. Blockage of Kv4 channels results in broader action potentials hence extended repolarization periods, the re-firing of the neuron is delayed. The amount of calcium ions entering a cell is regulated by the rate of repolarization. Neuron death may occur in extended repolarization periods when lots of calcium ions enter the cell, this may develop into strokes and seizures. 

Kv4 channels may be up regulated by Kv1 channels which cause repolarization of pyramidal neurons. Kv2 channels on the other hand have no effect on neuron repolarization rates.  

Repolarization of Ventricles

On analyzing an ECG, repolarization can be seen in several segments including the ST segment, J wave, T wave and U waves. Many physiological changes in the heart can have an effect on repolarization. This is due to the fact that that the heart has a very complex structure. Many drugs also have an effect on the repolarization in the heart. Studying the initial action potentials can also give us some information about the effects of repolarization by certain components. 

Studies show that the duration of action potentials must be 40-60 msec for action potentials stimulated in the epicardium in order to achieve an upright T-wave. A lower duration e.g. a 40-60 msec action potential duration will result in an isoelectric wave. An action potential below 20 msec would be seen to give a negative T-wave. Hence duration and location of initial action potentials is also seen to effect repolarization. 

When there is a large outward current in the epicardium in comparison to the endocardium, we get what is called as a J wave. In these J waves there is an elevated ST segment, this is an example of early repolarization. This early repolarization occurs predominantly in males. It is caused by the testosterone hormone and has a larger potassium current. There in an increased chance of cardiac arrest in these cases. Early repolarization is also found more commonly in African Americans.

Early Repolarization Syndrome

Early repolarization syndrome can also be called as sudden cardiac death. This condition appears in ventricular fibrillation without any other structural defects. This may also appear in early depolarization patterns. Genetics factors may cause electrical conductance malfunctions in ion channels which is the root cause of early repolarization syndrome. 

Some of the malfunctions include fluctuating currents of potassium, sodium, and calcium ions. These current changes may cause myocardial region to overlap undergoing different action potential phases simultaneously. This causes an increased risk of ventricular arrhythmias and fibrillation. 

However early repolarization syndrome is not a life-threatening condition. Many health individuals are found to have early repolarization on their ECGs. 

An implantable cardioverter-defibrillator is however recommended in patients who have early repolarization or have survived an early repolarization attack. Early repolarization syndrome patients and patients below the age of 60 are more likely to have atrial fibrillation. Isoproterenol is another suggested medication to be used in early repolarization syndrome.

Obstructive Sleep Apnea

Obstructive sleep apnea patients are known to have impaired cardiac repolarization, this increases the morbidity and mortality of this condition. Repolarization disturbances are also more common at high altitudes. Acetazolamide is known to decrease the severity of these disturbances and hence is commonly used. Acetazolamide does this by improving sleep apnea and oxygenation for these patients at high altitudes, however these effects are only temporary.

Conclusion 

Repolarization is just one stage of an action potential however it carries a significant role and disturbances may have drastic side effects. 

An action potential in neurons starts off with depolarization which is the opening of sodium ion channels which causes an influx of sodium ions raising the membrane potential from its resting membrane potential of -70mV to +40mV.

On closing of sodium ion channels at +40mv, the voltage gated potassium ion channels causing potassium ion efflux from the neuron causing the membrane potential to drop back down to -70mV. At -70mV, the neuron is said to enter a hyperpolarized state. 

In this hyperpolarized state the cell membrane potential further drops to a membrane potential to about -75mV after which the voltage gated potassium ion channels close and the sodium/potassium ATPases returns the membrane potential to its resting membrane potential of -70mV. 

The cell is no longer in a hyperpolarized state and is able to elicit its next action potential. 

The key channel involved in hyperpolarization is the voltage gated potassium ion channel. 

There are 4 variants of this channel namely the Kv1, Kv2, Kv3 and Kv4 channels. 

Different channels have different properties having different rates of activation and distributed in different parts of the nervous system. 

For example, the basal ganglia, hippocampus, and brainstem containing a larger number of Kv3 channels. 

The structure of these channels also gives us a lot of information about their voltage responses and conformations, respectively. 

Physiological changes in the heart are also able to affect repolarization, studying an ECG gives us information about this repolarization by looking at the J waves, ST segment, T waves and U waves. 

Many drugs may also affect repolarization in the heart. 

Early repolarization is more commonly in males, in African Americans and is caused by testosterone. Early repolarization syndrome/sudden cardiac arrest may be due genetic factors causing malfunctions in electrical conductance of ion channels. These patients are recommended an implantable cardioverter defibrillator, they are also recommended isoproterenol for treatment. 

Obstructive sleep apnea patients may also suffer cardiac repolarization issues, they are suggested Acetazolamide to reduce the severity of their symptoms. Repolarization disturbances are common at high altitudes.

References

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