Chapter 2: Ionic mechanisms and activity Potentials

John H. Byrne, Ph.D., department of Neurobiology and Anatomy, McGovern clinical School revised 05 January 2021

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2.1 Ionic mechanisms of action Potentials

Voltage-Dependent Conductances

Na+ is vital for the action potential in nerve cells. As shown in figure 2.1, action potentials are consistently initiated together the extracellular concentration the Na+ is modified. Together the concentration of salt in the extracellular solution is reduced, the activity potentials come to be smaller.

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Figure 2.2 mirrors the straight line predicted by the Nernst equation (assuming the membrane was solely permeable come Na+). There is a good fit in between the data and the values predicted through a membrane that is solely permeable to Na+. The experiment gives speculative support come the id that at the height of the activity potential, the membrane becomes extremely permeable to sodium.

However, there space some deviations between what is measured and what is suspect by the Nernst equation. Why? One factor for the deviation is the ongoing K+ permeability. If there is ongoing K+ permeability, the membrane potential will never ever reach its appropriate value (the salt equilibrium potential) due to the fact that the diffusion the K+ ions often tends to make the cabinet negative. This suggest can be understood with the assist of the GHK equation.


Figure 2.3


An action potential is bounded by a an ar bordered ~ above one too much by the K+ equilibrium potential (-75 mV) and on the other excessive by the Na+ equilibrium potential (+55 mV). The resting potential is -60 mV. Note that the resting potential is no equal come the K+ equilibrium potential because, as debated previously, there is a little resting Na+ permeability that renders the cabinet slightly more positive than EK. In principle, any allude along the trajectory of action potential deserve to be obtained simply by differing alpha in the GHK equation. If alpha is really large, the Na+ terms dominate, and according come the GHK equation, the membrane potential will relocate towards the Na+ equilibrium potential. The top of the action potentials approaches however does not quite reach ENa, since the membrane retains its permeability to K+.

How is it feasible for a cell to initially have a relaxing potential that -60 mV and also then, in solution to some stimulus (a short transient depolarization which reaches threshold), adjust in less than one millisecond to having actually a potential of around +40 mV? In the 1950"s, Hodgkin and also Huxley, two British neurobiologists, listed a hypothesis for this transition. They suggested that the nature of some Na+ channels in nerve cell (and muscle cells) were distinct in the these networks were typically closed but could be opened by a depolarization. This an easy hypothesis the voltage-dependent Na+ networks goes a long means toward explaining the initiation that the action potential. Mean a tiny depolarization reasons some that the Na+ channels to open. The an essential point is the the rise in Na+ permeability would create a higher depolarization, which will lead to an also greater variety of Na+ channels opening and the membrane potential becoming even an ext depolarized. Once some an important level is got to a hopeful feedback or regenerative cycle will certainly be initiated, bring about the membrane potential come depolarize swiftly from -60 mV to a worth approaching the Na+ equilibrium potential.


In stimulate to check the Na+ hypothesis for the initiation of the action potential, the is essential to stabilize the membrane potential at a variety of different levels and measure the permeability in ~ those potentials. An electronic machine known as a voltage-clamp amplifier deserve to "clamp" or stabilize the membrane potential to any desired level and measure the resultant current required for that stabilization. The lot of present necessary come stabilize the potential deserve to then be provided to quantify membrane permeability. Hodgkin and also Huxley clamped the membrane potential to assorted levels and also measured the alters in Na+ conductances (an electric term because that permeability, which for the current discussion deserve to be supplied interchangeably). The more the cell is depolarized, the better is the Na+ conductance. Thus, the experiment provided support because that the presence of voltage-dependent Na+ channels.

2.2 Na+ Inactivation

figure 2.4 likewise indicates vital property that the voltage-dependent Na+ channels. Note that the permeability boosts rapidly and also then, in spite of the fact that the membrane potential is clamped, the permeability decays earlier to its early level. This phenomenon is referred to as inactivation. The Na+ channels start to close, also in the ongoing presence of the depolarization. Inactivation contributes to the repolarization of the activity potential. However, inactivation is not enough by chin to account totally for the repolarization.

2.3 Voltage-Dependent K+ Conductance


In addition to voltage-dependent transforms in Na+ permeability, there space voltage-dependent changes in K+ permeability. These alters can it is in measured v the voltage-clamp technique as well. The figure shown to above indicates the transforms in K+ conductance and also the Na+ conductance. There space two necessary points.

First, just as there are channels in the membrane that room permeable come Na+ the are normally closed but then open in an answer to a voltage, there are also channels in the membrane that room selectively permeable to K+. This K+ channels are generally closed, however open in response to depolarization.

Second, a significant difference in between the alters in the K+ channels and the alters in the Na+ channels is that the K+ channels are slow to activate or open. (Some K+ channels also do no inactivate.) keep in mind that the return that the conductance in ~ the finish of the pulse is no the procedure of inactivation. With the removed of the pulse, the activated channels are deactivated.

2.4 succession of Conductance changes Underlying the Nerve activity Potential

part initial depolarization (e.g., a synaptic potential) will begin to open up the Na+ channels. The boost in the Na+ influx leads to a additional depolarization.


A positive feedback cycle rapidly moves the membrane potential towards its peak value, i m sorry is close however not equal to the Na+ equilibrium potential. Two processes which contribute to repolarization in ~ the top of the activity potential room then engaged. First, the Na+ conductance starts to decrease due to inactivation. Together the Na+ conductance decreases, an additional feedback bicycle is initiated, however this one is a downward cycle. Sodium conductance decreases, the membrane potential begins to repolarize, and the Na+ networks that space open and also not however inactivated are deactivated and also close. Second, the K+ conductance increases. Initially, over there is very little change in the K+ conductance since these channels are sluggish to open, however by the optimal of the action potential, the K+ conductance begins to boost significantly and also a 2nd force contributes come repolarization. As the an outcome of these 2 forces, the membrane potential promptly returns to the relaxing potential. At the moment it will -60 mV, the Na+ conductance has returned come its early stage value. Nevertheless, the membrane potential becomes an ext negative (the undershoot or the hyperpolarizing afterpotential).

The an essential to expertise the hyperpolarizing afterpotential is in the slowness of the K+ channels. Just as the K+ channels are sluggish to open (activate), they are additionally slow come close (deactivate). As soon as the membrane potential starts come repolarize, the K+ channels start to close due to the fact that they feeling the voltage. However, even though the membrane potential has actually returned come -60 mV, several of the voltage-dependent K+ channels remain open. Thus, the membrane potential will be much more negative than it to be initially. Eventually, these K+ channels close, and also the membrane potential returns to -60 mV.

Why go the cell go with these intricate mechanisms to generate an activity potential v a quick duration? Recall how information is coded in the worried system. If the action potential was around one msec in duration, the frequency of action potentials could change from as soon as a second to a thousands a second. Therefore, short action potentials carry out the nerve cell through the potential for a huge dynamic range of signaling.

2.5 Pharmacology of the Voltage-Dependent Membrane networks

 

part chemical agents can selectively block voltage-dependent membrane channels. Tetrodotoxin (TTX), which comes from the Japanese puffer fish, blocks the voltage-dependent alters in Na+ permeability, however has no result on the voltage-dependent transforms in K+ permeability. This observation indicates that the Na+ and K+ networks are unique; one of these have the right to be selectively blocked and also not influence the other. An additional agent, tetraethylammonium (TEA), has no result on the voltage-dependent transforms in Na+ permeability, yet it completely abolishes the voltage-dependent alters in K+ permeability.


usage these 2 agents (TTX and TEA) to test your understanding of the ionic mechanisms of the action potential. What result would dealing with an axon v TTX have on an action potential? An action potential would not occur due to the fact that an action potential in one axon cannot be initiated there is no voltage-dependent Na+ channels. Exactly how would TEA affect the activity potential? It would be longer and would not have actually an undershoot.

In the presence of TEA the initial step of the activity potential is identical, but note the it is much longer and does not have an after-hyperpolarization. Over there is a repolarization phase, yet now the repolarization is as result of the process of Na+ inactivation alone. Keep in mind that in the visibility of TEA, over there is no readjust in the relaxing potential. The channels in the membrane that endow the cell with the relaxing potential are different from the ones that are opened by voltage. They room not blocked by TEA. TEA only affects the voltage-dependent transforms in K+ permeability.

2.6 Pumps and also Leaks

the is easy to receive the impression the there is a "gush" of Na+ the comes right into the cell with each activity potential. Although, over there is part influx that Na+, that is minute contrasted to the intracellular concentration the Na+. The influx is inadequate to make any kind of noticeable adjust in the intracellular concentration the Na+. Therefore, the Na+ equilibrium potential walk not change during or ~ an activity potential. For any kind of individual activity potential, the lot of Na+ that comes into the cell and the quantity of K+ that leaves are insignificant and have no result on the bulk concentrations. However, without some compensatory mechanism, over the irreversible (many spikes), Na+ influx and K+ efflux would start to change the concentrations and also the resultant Na+ and K+ equilibrium potentials. The Na+-K+ pumps in nerve cells carry out for the permanent maintenance of this concentration gradients. They store the intracellular concentrations of K+ high and also the Na+ low, and thereby keep the Na+ equilibrium potential and the K+ equilibrium potential. The pumps are essential for the long-term maintenance that the "batteries" for this reason that relaxing potentials and activity potentials deserve to be supported.

2.7 varieties of Membrane Channels

so far, two straightforward classes the channels, voltage-dependent or voltage-gated channels and also voltage-independent channels, have been considered. Voltage-dependent channels can be more divided based on their permeation properties right into voltage-dependent Na+ channels and also voltage-dependent K+ channels. Over there are likewise voltage-dependent Ca2+ networks (see chapter on Synaptic Transmission). Indeed, there space multiple varieties of Ca2+ channels and voltage-dependent K+ channels. Nevertheless, every these channels are conceptually similar. They room membrane channels that are normally closed and as a an outcome of alters in potential, the channel (pore) is opened. The amino mountain sequence that these channels is recognized in significant detail and details amino acid sequences have been related to details aspects of channel function (e.g., ion selectivity, voltage gating, inactivation). A third major channel class, the transmitter-gated or ligand-gated channels, will certainly be defined later.

2.8 Channelopathies

Ion channel mutations have actually been established as a feasible cause that a wide range of inherited disorders. Several disorders including muscle membrane excitability have actually been connected with mutations in calcium, sodium and chloride channels and also acetylcholine receptors and have been labeled ‘channelopathies’. The is feasible that motion disorders, epilepsy and headache, as well as other rarely inherited diseases, could be connected to ion channels. The manifestations and mechanisms the channelopathies influence neurons space reviewed in Kullman, 2002. The presence of channelopathies may administer insights into the selection of moving mechanisms associated with the misfunctioning that neuronal circuits.

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2.9 Absolute and Relative Refractory Periods

The absolute refractory period is a duration of time after the initiation of one activity potential as soon as it is difficult to start a second action potential no matter how much the cabinet is depolarized. The relative refractory period is a duration after one activity potential is initiated when it is possible to initiate a 2nd action potential, but only v a better depolarization 보다 was necessary to initiate the first. The relative refractory period can be taken at the very least in part by the hyperpolarizing afterpotential. Assume the an initial stimulus depolarized a cell from -60 mV to -45 mV in order to with threshold and then take into consideration delivering the same 15-mV economic stimulation sometime throughout the after-hyperpolarization. The stimulus would certainly again depolarize the cell yet the depolarization would be below threshold and insufficient to cause an activity potential. If the stimulus was made larger, however, such the it again was qualified of depolarizing the cell to threshold (-45 mV), an action potential could be initiated.

The pure refractory duration can be described by the dynamics the the process of Na+-inactivation, the features of i m sorry are depicted in figure 2.10. Here, two voltage clamp pulses room delivered. The an initial pulse produces a voltage-dependent increase in the Na+ permeability which then undergoes the procedure of inactivation. If the two pulses are separated saturated in time, the 2nd pulse produce a readjust in the Na+ conductance, which is similar to the first pulse. However, if the 2nd pulse comes soon after the an initial pulse, climate the readjust in Na+ conductance developed by the second pulse is less than that created by the first. Indeed, if the second pulse occurs immediately after the first pulse, the 2nd pulse to produce no readjust in the Na+ conductance. Therefore, as soon as the Na+ networks open and also spontaneously inactivate, the takes time (several msec) because that them to recuperate from that inactivation. This process of restore from inactivation underlies the absolute refractory period. During an action potential the Na+ networks open and then they become inactivated. Therefore, if a second stimulus is ceded soon ~ the one that initiated the first spike, there will be couple of Na+ channels accessible to be opened by the second stimulus since they have actually been inactivated by the very first action potential. The pure refractory period seems like a fairly unimportant phenomenon, yet actually it is important to for sure unidirectional propagation of action potentials along axons.