Today we have a post by Mark Baker and Lavinia Austerschmidt (Blizard Institute Queen Mary University of London)
As you may know transport of sodium ions into nerves is a key mechanisms that allows nerves to transmit nerve impulses or action potentials. The action potential is the result of ions moving in and out of the cell. Specifically, it involves potassium (K+) and sodium (Na+) ions. The ions are moved in and out of the cell by potassium channels, sodium channels and the sodium-potassium pump. Today we hear from Mark Baker who talks about thier new work on the activities of sodium ions in MS.
We all know how sensitive pwMS are to changing body temperature, where a rise in core temperature can exacerbate symptoms (Uhthoffs phenomenon)
It is probable that small changes in body temperature (for example less than a degree centigrade) must affect function and also that such changes may be tangled up with the widespread problem of fatigue.
However, until recently no really convincing mechanism for such common and debilitating effects has been described, because it is likely to involve a mechanism widespread in the central nervous system and so able to affect a variety of functions, including both our sensations and ability to move.
However, we, funded by the MS society, have uncovered a mechanism based on sodium ion transport (sodium is part of common salt and is plentiful in the body) on transporter proteins not involved in generating nerve impulses. In fact, the transport of sodium makes the nerve fibres less excitable and the transport mechanism must move other charged ions or molecules in parallel with the sodium.
As the amount of transport is expected to increase with rising temperature, larger increases in temperature will bring about larger falls in nerve excitability. Making damaged nerve fibres less excitable would be expected to have serious consequences, such as loss of nerve impulse conduction, and so loss of function. This work culminated in an understanding published in a previous paper Austerschmidt et al (2020) (10.1038/s41598-020-69728-y)
Austerschmidt LJ, Khan A, Plant DO, Richards EMB, Knott S, Baker MD. The effects of temperature on the biophysical properties of optic nerve F-fibres. Sci Rep. 2020 Jul 29;10(1):12755. doi: 10.1038/s41598-020-69728-y
This quantified by how much axons in the optic nerve are affected by a rising temperature.
In the new paper by Austerschmidt et al (2021) https://rdcu.be/czyr4, we shed-light (literally) on the mechanism of temperature sensitivity in axons, by using infra-red light from a laser diode to illuminate optic nerve and locally to warm the axons. We found something that was expected, but also something that was unexpected. The application of the warming light does make the axons less excitable, however part of the change in excitability associated with the laser seems to be caused by a new, light-dependent, effect, possibly on the myelin. A slower effect that develops over minutes is on the axons directly, and this change appears equivalent to that reported before, with new information revealing how small changes in temperature, of the order of a single degree centigrade, can have measureable effects on nerve function.
Also, we help prove the mechanism of this action of infra-red light by using a chemical to modify the responsiveness of the axons (called ZD7288). The fact that the direct effect on the axons appears to take minutes to occur further underlines the probability that the transport of sodium ions, the process that brings about the fall in excitability, is relatively slow, even though the temperature change in the axons brought about by the laser, will be fast.
Uncovering the details of the molecular mechanisms bringing sodium ions into the nerve fibres (as shown in the figure) may offer hope for the development of a treatment for temperature sensitivity.
This is how the envisaged system works. Sodium ions (Na+) enter the nerve fibre on a transporter system (blue) that brings other ions, and, or molecules across the cell membrane at the same time (indicated as O-). The key things are that this transport system does not pass a current, because no net charge goes across the membrane, and that this transport speeds up with warming. The sodium exits the nerve fibre via an enzyme (protein) called the sodium-pump (red) that exchanges the sodium (Na+) for potassium ions (K+). Because the charge exchange is asymmetric (uneven), the nerve fibre will inevitably become less excitable if the pump activity increases.
Austerschmidt LJ, Schottler NI, Miller AM, Baker MD. Changing the firing threshold for normal optic nerve axons by the application of infra-red laser light. Sci Rep. 2021 Oct 15;11(1):20528. doi: 10.1038/s41598-021-00084-1.
Normal optic nerve axons exhibit a temperature dependence, previously explained by a membrane potential hyperpolarization on warming. We now report that near infra-red laser light, delivered via a fibre optic light guide, also affects axonal membrane potential and threshold, at least partly through a photo-thermal effect. Application of light to optic nerve, at the recording site, gave rise to a local membrane potential hyperpolarization over a period of about a minute, and increased the size of the depolarizing after potential. Application near the site of electrical stimulation reversibly raised current-threshold, and the change in threshold recorded over minutes of irradiation was significantly increased by the application of the Ih blocker, ZD7288 (50 µM), indicating Ih limits the hyperpolarizing effect of light. Light application also had fast effects on nerve behaviour, increasing threshold without appreciable delay (within seconds), probably by a mechanism independent of kinetically fast K+ channels and Na+ channel inactivation, and hypothesized to be caused by reversible changes in myelin function.
CoI: None relevant