Saturday, 27 May 2017

GABA and Remyelination-Its Confusing I know but no cause for concern

Yesterday I caused a bit of concern by a post on myelination as a GABA (inhibitory nerve transmitter) blocker stimulated developmental myelination, so people were worried about their GABA receptor stimulating drugs. Would they block repair? Answer is I do not definitively know but suspect not.

In contrast there could be implications that stimulation of GABA could save nerves. Again we don't have the data.

I will try explain a bit, but it is very, very complicated.

First things first, the report of GABAergic control of myelination is based on developmental myelination (myelinating nerves from the first time), and as the docs from Cambridge/Edinburgh have shown remyelination may not be the same process as developmental myelination.

Next it is far more complex than just GABA. What else has to be stimulated?

We have already been told that the oligodendrocyte precursor cells get stimulated by glutamate (excitatory nerve transmitter). This transmits their function via activity on glutamate receptors. Here there are lots of types, over twenty receptor genes.  There are three main ionotrophic (opens channels for electrically charged (ion) sodium calcium or potassium) subtypes AMPA, Kainate and NMDA binding subtypes

Myelination first acts via the AMPA sensitive variants, then their influence stops whilst the NMDA-sensitive subtypes come into play. This process will be influenced by the GABA receptors. This stimulates developmental maturation of the oligodendrocyte precursor cell and myelination of un-myelinated nerves. During this process the glutamate receptors and ion channels get down regulated. It is not the odd one, but loads of them.
Here are the potassium channels) or should I say some as I got bored and stopped at about M  ie. KCNM) but could have gone on eg N KCNN etc




Next there are more than one type of GABA receptor. There are two main types. One is GABA A and the other is GABAB. GABA A is an ionotrophic (via chloride) channel that can be stimulated by different types of drug as it has multiple sites and there are multiple genes making a multi-component receptor.




GABA B is a metabotrophic receptor which G protein coupled receptor that is linked signalling to control calcium channel activity and can signal via potassium channels.


Baclofen is the main GABA B receptor stimulator, used for spasticity. GABApentin, Pregabalin look like GABA but do not bind to the GABA receptors, although they may influence GABA production they act via ion channels to be anti-convulsants and pain controllers. The story about GABA and oligodendrocytes involved GABA A receptors, so the story is not about these drugs

Indeed in the experimental study they blocked the GABA response with a drug called Gabazine (SR-95531). It is used in scientific research and has no role in medicine, as it would be expected to produce convulsions. 

Any drug used in humans would never block the GABA A receptor to the extent used in the experiments so a block would never happen in humans. Experimental studies often use crazy doses of drugs to show a theorhectic possibility or define a mechanism. But they have no translational value. 

If the authors had read the ARRIVE guidelines about reporting experimental studies, they could have talked about the translatable aspects and if they had used clinical concentrations of GABA A blocking drugs, I bet they would have shown nothing...Nothing does not make for a good publication. But until this expriment is done, no cause for concern.

The importance of this post was to show that oligodendrocytes have ionotrophic function and they have loads of ion channels including loads of potassium channels.


8 comments:

  1. Copy and Paste Syndrome.

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    1. Sorry I respond full of rubbish syndrome, I have spent time adding links to wikipedia to help you understand, I have included two slides of totally original data analysis never seen before.

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  2. Hope this does not sound like a politician u turn.

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  3. Thank you very much for solving my confusion. :)))

    I really had this doubt but now I understand a little of what really happens. I will not continue to take my own Gabapentin when I have neuropathic pain, which I do not know why I have not had it.

    ReplyDelete

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