Proton-gated Ca(2+)-permeable TRP channels damage myelin in conditions mimicking ischaemia

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(1,2). This has been attributed to glutamate release activating Ca(2+)-permeable NMDA receptors(2-4). Surprisingly, we now show that NMDA does not raise [Ca(2+)](i) in mature oligodendrocytes and that, although ischaemia evokes a glutamate-triggered membrane current(4), 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 TRPA1-containing ion channels as a therapeutic target in white matter ischaemia.