Voltage-Gated+Channels+and+Action+Potentials

=**Voltage-Gated Channels and Action Potentials**=


 * 1. Define action potential nomenclature: resting potential, threshold, depolarizing phase, overshoot, hyperpolarizing phase, after hyperpolarization.**

__Resting potential:__membrane potential that would be maintained if there were no action potentials, synaptic potentials, or other active changes in the membrane potential. At resting potential some potassium leak channels are open but the voltage-gated sodium channels are closed. Even though no net current is flowing, the major ion species moving across the membrane is potassium, thus pulling the resting potential close to the K+ equilibrium potential.

__Threshold:__ the level of depolorization needed to activate voltage gated ion channels.

__Depolarizing phase:__ voltage-gated sodium channels in the neuron cell surface membrane to open and therefore sodium ions diffuse in through the channels along their electrochemical gradient. As sodium ions enter and the membrane potential becomes less negative, more sodium channels open, causing an even greater influx of sodium ions. This is an example of positive feedback.

__Overshoot:__ As more sodium channels open, the sodium current dominates over the potassium leak current and the membrane potential becomes positive inside.

__Hyperpolarizing phase: __By the time the membrane potential has reached a peak value of around +30 mV voltage-sensitive inactivation gates on the sodium channels have already started to close, reducing and finally preventing further influx of sodium ions. While this occurs, the voltage-sensitive activation gates on the voltage-gated potassium channels begin to open. As voltage-gated potassium channels open, there is a large outward movement of potassium ions driven by the potassium concentration gradient and initially favored by the positive-inside electrical gradient. As potassium ions diffuse out, this movement of positive charge causes a reversal of the membrane potential to negative-inside and repolarization of the neuron back towards the large negative-inside resting potential.

__After hyperpolarization:__Closing of voltage-gated potassium channels is both voltage-dependant and time-dependent. As potassium exits the cell, the resulting membrane repolarization initiates the closing of voltage gated potassium channels. These channels do not close immediately in response to a change in membrane potential. Rather, voltage-gated potassium channels have a delayed response, such that potassium continues to flow out of the cell even after the membrane has fully repolarized. Thus the membrane potential dips below the normal resting membrane potential of the cell for a brief moment.


 * 2. Describe general features common to voltage-gated Na+, Ca2+, and K+ channels and recognize the key structural elements that give the channels their specific properties: voltage dependence, gating, ion selectivity, and inactivation.**

Sodium channels are composed of a complex of two types of protein subunits, α and β, potassium channels are similar in structure with the 4 subunits homologous to 4 α domians in the Na channel. Calcium channels have a similar structure with functional heterogenicity. An α subunit forms the core of the channel, and the β subunit which act as a reulatory region. The α-subunit has four repeat domains, labeled I through IV, each containing six membrane-spanning regions. The four α domains arange themselve to form a aqueous pore with a narrow selectivity filter at its opening. A subunit of the α domain acts as a voltage sensor activating a gate that limits the flow of ions. Below this gate lies an inactivating region that acts to secondarily block the pore once it is opened.


 * 3. Describe how ion flow through voltage-sensitive Na+ and K+ channels produces macroscopic membrane currents which also show features of activation and inactivation, and, when combined with appropriate kinetic parameters, produces an action potential.**

When a positive current is injected into the neuron, the probability of opening voltage-gated Na+ and K+ channels changes. For small depolarizations below the threshold level, the neuron is depolarized just enough so that a few Na+ channels open, permitting entry of some Na+ ions and increasing the net positive charge within the axon. This in turn increases the probability that still more Na+ channels will open (positive feedback). The same initial depolarization also opens voltage-dependent K+ channels which adds to the total K+ permeability (also contributed by other types of K+ channels which may be open such as K+ leak channels). The increased internal positive charge favors efflux of K+ ions through these open channels to lessen the internal positive charge (negative feedback).

Many of the Na+ channels tend to open all at about the same time at the initiation of the voltage pulse and then quickly become inactivated, preventing further conduction of Na+ ions. One a particular channel has been activated (opened) and become inactivated, it will not immediately open a second time, even if the depolarizing voltage is still applied. The K+ influx last longer than the Na+ influx because the voltage-gated K+ channels do not inactivate. The probability of voltage-gated K+ channels opening increases in a sigmoid relationship to membrane voltage just like voltage-gated Na+ channels, but Na+ peaks quickly after the initial depolarization and shuts off while K+ channels peak more slowly and plateau until the end of depolarization.

Exactly at the threshold voltage, each Na+ ion that enters and contributes one positive charge is counterbalanced by a lost of one K+ ion. So at threshold, the net charge movement is zero; however, this is an unstable situation and just one extra charge flowing in either direction may be adequate to trigger a regenerative, self-sustaining increase in Na+ conductance and an action potential or may lead to reduced K+ conductance and eventual return to resting membrane potential.


 * 4. Explain the concepts of threshold and refractory period in terms of events at the level of single channels and ions.**

Threshold is the level of depoerization needed for the voltage sensor in the α-subunit to open the gate blocking the ion channel. Following the opening of this channel ions rush in and the channel is then closed by an inactivator. While the inactivator is in place no ions can pass and the channel is in a refractory period. Once the voltage gate is reset and the inactivator is removed the ion is again able to open.

Absolute refractory period is if, following the 1st action potential, a subsequent depolarization, no matter how large, is incapable of eliciting a second action potential. Relative refractory period is if a second action potential can be evoked but requires more stimulus current than would be needed had there been no preceding action potential.


 * 5. Define the concept of "length constant" and describe how this relates to current flow from one region of an axon to adjacent membrane areas.**

The length constant is the distance along which passive ionic current can flow along an axon or dendrite. As the depolarization wave travels down the membrane some escapes through "leakage" channels making the depolarization weaker as it goes. The main reason is that the axial resistance of the axon lumen is lower with larger diameters, because of an increase in the ratio of cross-sectional area to membrane surface area.

Unlike potentials produced by passive currents, action potentials do not decrement over distance since they are self-renewing at each point along the axon, but the speed of the action potential is very much dependent on how far down the axon it can induce current flow and charge up the membrane.


 * 6. Describe how action potentials are conducted into myelinated and unmyelinated axons, and explain how demyleinating disease affects conduction of action potentials.**

In myelinated axons, the myelin layer increases membrane resistivity, making them better conductors than unmyelinated axons. In unmylinated axons, Na+ channels are located all along the length of the axon. However, in myelinated axons, the internodal segments have few Na+ channels and more K+ channels. Saltatory conduction is the process by which an action potential appears to jump along the length of an axon, being regenerated only at uninsulated segments, the nodes of Ranvier.

This works because the action potential is a focal points of charge transfer, and it only need to partially activate the Na+ channels over the threshold in the adjacent section of membrane to trigger a full scale action potential at that point. This process occurs at each point along the axon, producing a traveling wave of transmembrane voltage in front of it and a refractory region of diminished sensitivity behind it so that the action potential doesn’t reverse itself midstream. Saltatory conduction increases nerve conduction velocity without having to dramatically increase axon diameter.

In demyelinating disease, the spread of current may be reduced and the nodes of Ranvier may be less effective. In unmyelinated axons, Na+ channels are evenly distributed along the length of the axon. However, the inter-node segments of myelinated fibers have a scarcity of Na+ channels and an increased density of K+ channels. This results in a high threshold for action potential initiation and current leakage through the membrane where there are not sufficient Na+ and K+ channels to regenerate the action potential downstream.

Also, the clustering of Na+ channels at nodes and K+ channels between nodes are anchored to the axon’s cytoskeleton by factors from oligodendrocytes/Schwann cells but are not maintained by them. This means that myelinated axons of the CNS cannot revert back to non-saltatory conduction after acute demylination. Eventually, new Na+ channels must be synthesized and redistributed, but the properties of these channels may differ from normal and the axon membrane may be damaged from inflammatory processes of autoimmune response and phagocytotic clearing of myelin debris.


 * 7. Predict how effective neurons exhibit spatial summation of non-propagated currents based on knowledge of the space constant.**

Passive current flow through dendrites dissipates with distance, just as in axons. This resistance to current determines the effectiveness of excitatory or inhibitory postsynaptic potentials (EPSP or IPSP) because they cannot actively propagate and self-renew like action potentials. These low potentials can arise at synapses positioned at different distances along dendrites and have unequal influence on the voltage at the soma.

Synapses closer to the cell body are more effective than distant synapses on the same dendrite. Thicker dendrites with fewer branches and less taper transmit current more effectively than thin, highly branched, rapidly tapering dendrites.

When a group of synapses are simultaneously activated, each will contribute an amount of current flow toward the cell body in proportion to its distance and effective space constant of the dendrites separating the synapse from the soma. This combining of currents from synapses at different locations in a neuron is called spatial summation.


 * 8. Explain what is meant by the time constant of a neuron and describe how temporal summation transforms neural signals from a frequency code to an amplitude code.**

The resistively of the axon membrane and its capacitance in parallel determines how quickly a passive voltage change will occur across the neuron membrane. That is, lipid membranes store charge and behave like capacitors; neurons are electrical filters with time constant &tau; ``=`` RC. A rectangular current pulse across the membrane produces an exponential voltage change described by &tau; until the capacitance is fully charged.

The slow charging and discharging of neuron membrane capacitance allows for temporal summation of EPSPs, allowing separate EPSPs to add together if they arrive at a rate close to 1 / &tau;.

The relatively small cross sectional area of axons means that an action potential can quickly charge up the capacitance of the next small section of membrane and this brief charging period is negligible as far as action potential conduction is concerned. That is, the length constant of the axons has much bigger effect on action potential conduction velocity than does the time constant.

The membrane time constant also acts as a temporal filter to smooth out timing information in varying frequency discharges of incoming action potentials. The low-pass filter effect of the dendrite’s time constant reduces the jagged components of individual action potential timing, emphasizing the much slower, summated potentials. This result in an amplitude modulation of voltage that matches the average input frequency of presynaptic action potentials. In electrical terms, the consequence of temporal summation is that information coded as action potential frequency is converted into an analogue voltage proportional to the input frequency.