In neuroscience, repolarization refers to the change in membrane potential that returns it to a negative value just after the depolarization phase of an action potential which has changed the membrane potential to a positive value. The repolarization phase usually returns the membrane potential back to the resting membrane potential. The efflux of potassium (K+) ions results in the falling phase of an action potential. The ions pass through the selectivity filter of the K+ channel pore. Repolarization typically results from the movement of positively charged K+ ions out of the cell. The repolarization phase of an action potential initially results in hyperpolarization, attainment of a membrane potential, termed the afterhyperpolarization, that is more negative than the resting potential. Repolarization usually takes several milliseconds. Repolarization is a stage of an action potential in which the cell experiences a decrease of voltage due to the efflux of potassium (K+) ions along its electrochemical gradient. This phase occurs after the cell reaches its highest voltage from depolarization. After repolarization, the cell hyperpolarizes as it reaches resting membrane potential (−70 mV in neuron). Sodium (Na+) and potassium ions inside and outside the cell are moved by a sodium potassium pump, ensuring that electrochemical equilibrium remains unreached to allow the cell to maintain a state of resting membrane potential. In the graph of an action potential, the hyper-polarization section looks like a downward dip that goes lower than the line of resting membrane potential. In this afterhyperpolarization (the downward dip), the cell sits at more negative potential than rest (about −80 mV) due to the slow inactivation of voltage gated K+ delayed rectifier channels, which are the primary K+ channels associated with repolarization. At these low voltages, all of the voltage gated K+ channels close, and the cell returns to resting potential within a few milliseconds. A cell which is experiencing repolarization is said to be in its absolute refractory period. Other voltage gated K+ channels which contribute to repolarization include A-type channels and Ca2+-activated K+ channels. Protein transport molecules are responsible for Na+ out of the cell and K+ into the cell to restore the original resting ion concentrations.
Deviations from normal repolarization Blockages in repolarization can arise due to modifications of the voltage-gated K+ channels. This is demonstrated with selectively blocking voltage gated K+ channels with the antagonist tetraethylammonium (TEA). By blocking the channel, repolarization is effectively stopped. Dendrotoxins are another example of a selective pharmacological blocker for voltage gated K+ channels. The lack of repolarization means that neuron stays at a high voltage, which slows sodium channel deactivation to a point where there is not enough inwards Na+ current to depolarize and sustain firing.
Voltage gated K+ mechanisms The structure of the voltage gated K+ channel is that of six transmembrane helices along the lipid bilayer. The selectivity of this channel to voltage is mediated by four of these transmembrane domains (S1–S4) – the voltage sensing domain. The other two domains (S5, S6) form the pore by which ions traverse. Activation and deactivation of the voltage gated K+ channel is triggered by conformational changes in the voltage sensing domain. Specifically, the S4 domain moves such that it activates and deactivates the pore. During activation, there is outward S4 motion, causing tighter VSD-pore linkage. Deactivation is characterized by inward S4 motion. The switch from depolarization into repolarization is dependent on the kinetic mechanisms of both voltage gated K+ and Na+ channels. Although both voltage gated Na+ and K+ channels activate at roughly the same voltage (−50 mV), Na+ channels have faster kinetics and activate/deinactivate much more quickly. Repolarization occurs as the influx of Na+ decreases (channels deinactivate) and the efflux of K+ ions increases as its channels open. The decreased conductance of sodium ions and increased conductance of potassium ions cause the cell's membrane potential to very quickly return to, and past the resting membrane potential, which causes the hyperpolarization due to the potassium channels closing slowly, allowing more potassium to flow through after the resting membrane potential has been reached.
Type of K+ channels in repolarization Following the action potential, characteristically generated by the influx of Na+ through voltage gated Na+ channels, there is a period of repolarization in which the Na+ channels are inactivated while K+ channels are activated. Further study of K+ channels shows that there are four types which influence the repolarization of the cell membrane to re-establish the resting potential. The four types are Kv1, Kv2, Kv3 and Kv4. The Kv1 channel primarily influences the repolarization of the axon. The Kv2 channel is characteristically activated slower. The Kv4 channels are characteristically activated rapidly. When Kv2 and Kv4 channels are blocked, the action potential predictably widens. The Kv3 channels open at a more positive membrane potential and deactivate 10 times faster than the other Kv channels. These properties allow for the high-frequency firing that mammalian neurons require. Areas with dense Kv3 channels include the neocortex, basal ganglia, brain stem and hippocampus as these regions create microsecond action potentials that requires quick repolarization. Utilizing voltage-clamp data from experiments based on rodent neurons, the Kv4 channels are associated with the primary repolarization conductance following the depolarization period of a neuron. When the Kv4 channel is blocked, the action potential becomes broader, resulting in an extended repolarization period, delaying the neuron from being able to fire again. The rate of repolarization closely regulates the amount of Ca2+ ions entering the cell. When large quantities of Ca2+ ions enter the cell due to extended repolarization periods, the neuron may die, leading to the development of stroke or seizures. The Kv1 channels are found to contribute to repolarization of pyramidal neurons, likely associated with an upregulation of the Kv4 channels. The Kv2 channels were not found to contribute to repolarization rate as blocking these channels did not result in changes in neuron repolarization rates.
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