Proton-gated Ca.sup.2+-permeable TRP channels damage myelin in conditions mimicking ischaemia

Ischaemia damages nerve myelin by depriving neurons and their myelinating oligodendrocytes of oxygen and glucose; here it is shown that ischaemic damage is caused through the H.sup.+-dependent activation of TRPA1 channels, and not via glutamate receptors of the NMDA type, as previously thought, providing a new mechanism and promising therapeutic targets for diseases as diverse and prevalent as cerebral palsy, spinal cord injury, stroke and multiple sclerosis. TRP channels damaged in ischaemia Fast nerve conduction relies on the insulating sheaths of myelin produced by glial cells -- oligodendrocytes -- of the white matter. These cells can be damaged by deprivation of blood oxygen (ischaemia) during stroke and other circulatory disturbances. David Attwell and colleagues show that ischaemic damage to oligodendrocytes causes elevation of intracellular Ca.sup.2+ levels through H.sup.+-dependent activation of TRPA1 receptors, and not via glutamate receptors of the NMDA type, as previously thought. The results provide a new mechanism and promising therapeutic targets for diseases as diverse and prevalent as cerebral palsy, spinal cord injury, stroke and multiple sclerosis. The myelin sheaths wrapped around axons by oligodendrocytes are crucial for brain function. In ischaemia myelin is damaged in a Ca.sup.2+-dependent manner, abolishing action potential propagation.sup.1,2. This has been attributed to glutamate release activating Ca.sup.2+-permeable N-methyl-d-aspartate (NMDA) receptors.sup.2,3,4. Surprisingly, we now show that NMDA does not raise the intracellular Ca.sup.2+ concentration ([Ca.sup.2+].sub.i) in mature oligodendrocytes and that, although ischaemia evokes a glutamate-triggered membrane current.sup.4, this is generated by a rise of extracellular [K.sup.+] and decrease of membrane K.sup.+ conductance. Nevertheless, ischaemia raises oligodendrocyte [Ca.sup.2+].sub.i, [Mg.sup.2+].sub.i and [H.sup.+].sub.i, and buffering intracellular pH reduces the [Ca.sup.2+].sub.i and [Mg.sup.2+].sub.i increases, showing that these are evoked by the rise of [H.sup.+].sub.i. The H.sup.+-gated [Ca.sup.2+].sub.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.
Author(s): Nicola B. Hamilton [sup.1] , Karolina Kolodziejczyk [sup.1] [sup.2] , Eleni Kougioumtzidou [sup.1] , David Attwell [sup.1] Author Affiliations: (1) Department of Neuroscience, Physiology & Pharmacology, University College London, [...]