Migrating ion channels, part 2

In the following I continue the discussion of fatigue in multiple sclerosis and ion channels as promised at the end of a previous post. I start with a few more details concerning the mechanism of ordinary nerve conduction.In the resting state there is a potential difference across the cell membrane.There are sodium-potassium pumps in the cell membrane which simultaneously move potassium to the inside of the cell and sodium to the outside. This process is charge neutral. The membrane also contains ‘leak channels’ which allow diffusion of potassium ions. This process continues until the concentration difference is balanced by the charge difference leading to a zero electrochemical potential. Then the resting membrane potential has been established. If this potential is reduced by a sufficiently large amount at some point on the membrane voltage-gated sodium channels open and sodium ions flow into the cell, depolarizing the membrane. In fact the sign of the potential difference is even reversed. After some time the sodium channels enter a temporary inactive state where they do not allow ions to pass and do not react to voltage changes. In the meantime voltage-gated potassium channels open, also as a result of the depolarization, and lead to the membrane potential rapidly returning to its equilibrium value. Finally the sodium channels return to a state where they are closed but active. This completes the cycle. An action potential in an axon without myelin, like that of the squid, is a travelling wave where this cycle happens successively at successive spatial points.

In the case of a myelinated axon the depolarization of one node of Ranvier propagates to the next node at a very high speed, essentially the speed of light in the given medium, and the greatest part of the total time of propagation of the nerve impulse is spent near the nodes. The mechanisms described above are then only relevant in the region close to a node. Under these circumstances it is not surprising that the ion channels involved are concentrated near the node. Less obvious is the fact that the sodium channels sit at the node while the potassium channels are concentrated a small distance away. An axon which is demyelinated often conducts signals more slowly than an intact one and sometimes suffers a complete block of conduction. It is these problems which presumably cause fatigue. (Here I am talking about fatigue in the context of physical activity, or possibly vision, and not the mental fatigue which also affects MS sufferers and which is harder to pin down precisely.) A demyelinated neuron is often not able to fire repeatedly at more than a certain frequency or even to fire a few times in a row. These things are usually studied experimentally in the context of peripheral nerves since the central nervous system is so difficult of access.

The key question is now which mechanisms lie behind the malfunctioning of the demyelinated axons. A better understanding of this question could have implications for therapeutic strategies. One hypothesis is that the problem is that the membrane potential is too large due to an excessive concentration of sodium ions outside the cell. This is proposed in a paper of Bostock and Grafe (J. Physiol. 365, 239). They describe how repeated firing can lead to hyperpolarization in normal axons. In more detail, an initial reduction of the intracellular sodium concentration stimulates the sodium-potassium pumps which finally bring the extracellular sodium concentration to a level which is too high. In the case of demyelinated axons these mechanisms might lead to harmful effects. There the depolarization of one node produced by a depolarization of the previous one is dangerously close to the threshold for activation. Thus a small change of the membrane potential can produce failure. In this paper some work on numerical computations of the properties of demyelinated nerve fibres by Koles and Rasminsky (J. Physiol. 227, 351) is quoted. The description of the model given in that paper is not very self-contained and so understanding it would require going to the previous literature. In a later paper of Vagg. et. al. on this subject (J. Physiol. 507, 919) the repeated firing of neurons producing the effect is due to a sustained voluntary contraction of a muscle. This underlines how this type of mechanism could explain difficulties in maintaining muscular contraction.


One Response to “Migrating ion channels, part 2”

  1. hydrobates Says:

    I now noticed that the original post contained an error and an omission.The error was to claim the the action of the sodium-potassium pump is charge neutral. In fact the pump transfers three sodium ions and only two potassium ions in each cycle. This does not have a very large effect on the membrane potential since the resulting charge transfer is compensated by the influence of mobile chloride ions. These facts have been known for a long time – see for instance the Nobel lecture of Jens Skou, the discoverer of these pumps. The omission was that the parts of the cycle I described lead to a net change in the sodium and potassium concentrations. These must be reversed by the sodium-potassium pumps in order to restore the original state.

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