Publication Date:
2016-01-14
Description:
The myelin sheaths wrapped around axons by oligodendrocytes are crucial for brain function. In ischaemia myelin is damaged in a Ca(2+)-dependent manner, abolishing action potential propagation. This has been attributed to glutamate release activating Ca(2+)-permeable N-methyl-D-aspartate (NMDA) receptors. Surprisingly, we now show that NMDA does not raise the intracellular Ca(2+) concentration ([Ca(2+)]i) in mature oligodendrocytes and that, although ischaemia evokes a glutamate-triggered membrane current, this is generated by a rise of extracellular [K(+)] and decrease of membrane K(+) conductance. Nevertheless, ischaemia raises oligodendrocyte [Ca(2+)]i, [Mg(2+)]i and [H(+)]i, and buffering intracellular pH reduces the [Ca(2+)]i and [Mg(2+)]i increases, showing that these are evoked by the rise of [H(+)]i. The H(+)-gated [Ca(2+)]i elevation is mediated by channels with characteristics of TRPA1, being inhibited by ruthenium red, isopentenyl pyrophosphate, HC-030031, A967079 or TRPA1 knockout. TRPA1 block reduces myelin damage in ischaemia. These data suggest that TRPA1-containing ion channels could be a therapeutic target in white matter ischaemia.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4733665/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4733665/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hamilton, Nicola B -- Kolodziejczyk, Karolina -- Kougioumtzidou, Eleni -- Attwell, David -- Wellcome Trust/United Kingdom -- England -- Nature. 2016 Jan 28;529(7587):523-7. doi: 10.1038/nature16519. Epub 2016 Jan 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neuroscience, Physiology &Pharmacology, University College London, Gower St., London WC1E 6BT, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26760212" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Brain Ischemia/*metabolism/*pathology
;
Calcium/*metabolism
;
Calcium Signaling/drug effects
;
Electric Conductivity
;
Female
;
Hydrogen-Ion Concentration
;
Magnesium/metabolism
;
Male
;
Mice
;
Mice, Transgenic
;
Multiple Sclerosis/metabolism/pathology
;
Myelin Sheath/drug effects/*metabolism/*pathology
;
N-Methylaspartate/metabolism/pharmacology
;
Oligodendroglia/drug effects/metabolism/pathology
;
Potassium/metabolism
;
*Protons
;
Rats
;
Rats, Sprague-Dawley
;
Receptors, N-Methyl-D-Aspartate/metabolism
;
Stroke/metabolism/pathology
;
Transient Receptor Potential Channels/antagonists &
;
inhibitors/deficiency/genetics/*metabolism
;
White Matter/metabolism/pathology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
