title: Proton-gated Ca(2+)-permeable TRP channels damage myelin in conditions mimicking ischaemia.
abstract: 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.
authors.affiliation: Department of Neuroscience, Physiology &Pharmacology, University College London, Gower St., London WC1E 6BT, UK.
authors.forename: Nicola B
authors.initials: NB
authors.lastname: Hamilton
authors.affiliation: Department of Neuroscience, Physiology &Pharmacology, University College London, Gower St., London WC1E 6BT, UK.
authors.forename: Karolina
authors.initials: K
authors.lastname: Kolodziejczyk
authors.affiliation: Department of Neuroscience, Physiology &Pharmacology, University College London, Gower St., London WC1E 6BT, UK.
authors.forename: Eleni
authors.initials: E
authors.lastname: Kougioumtzidou
authors.affiliation: Department of Neuroscience, Physiology &Pharmacology, University College London, Gower St., London WC1E 6BT, UK.
authors.forename: David
authors.initials: D
authors.lastname: Attwell
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D004553:Electric Conductivity; D005260:Female; D006863:Hydrogen-Ion Concentration; D008274:Magnesium / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D016202:N-Methylaspartate / Q000378:metabolism / Q000494:pharmacology; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011188:Potassium / Q000378:metabolism; D011522:Protons; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D020521:Stroke / Q000378:metabolism / Q000473:pathology; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D066127:White Matter / Q000378:metabolism / Q000473:pathology
chemical_list: D011522:Protons; D016194:Receptors, N-Methyl-D-Aspartate; D050051:Transient Receptor Potential Channels; D016202:N-Methylaspartate; D008274:Magnesium; D011188:Potassium; D002118:Calcium