Editors' ChoiceNeuroscience

Toxic TRPA1 activity degrades myelin

Sci. Signal.  02 Feb 2016:
Vol. 9, Issue 413, pp. ec20
DOI: 10.1126/scisignal.aaf3611

Ischemia, deprivation of tissues of oxygen and nutrients due to loss of blood flow such as occurs during stroke, damages neurons and glia, including the myelin sheath produced by oligodendrocytes. Although cytotoxic influx of Ca2+ through NMDA-type glutamate receptors plays a key role in damaging neurons, Hamilton et al. provide evidence in rodents that oligodendrocyte damage involves the divalent cation–permeable channel TRPA1. Electrophysiological analysis, analysis with ion-selective electrodes, and ion-imaging analysis using ion-responsive dyes showed that rat oligodendrocytes in cerebellar slice preparations exhibited an ischemia-induced increase in intracellular H+, Ca2+, and Mg2+ and a decrease in K+ conductance. Furthermore, extracellular K+ increased. Removing extracellular Ca2+ or K+ abolished or reduced, respectively, the ischemia-induced increase in intracellular Ca2+ and H+ in the oligodendrocytes, indicating that the rise in intracellular Ca2+ resulted from Ca2+ influx, not release from intracellular stores, and that the change in K+ promoted this Ca2+ influx possibly by acidifying the cytosol. TRPA1 and TRPV3 are channels of the transient receptor potential (TRP) family that are activated by low pH. Experiments with pharmacological agonists and antagonists of TRPA1 and TRPV3 indicated that TRPA1 was involved in the H+-induced increase in oligodendrocyte intracellular Ca2+, a conclusion supported by experiments with slice preparations from Trpa1-knockout mice and the detection of TRPA1-encoding, but not TRPV3-encoding, transcripts in mature mouse oligodendrocytes. Using a rat optic nerve myelin damage model, blocking TRPA1 pharmacologically reduced ischemia-induced myelin damage, but did not prevent axon damage, indicating that glial injury and neuronal injury occurred through different molecular mechanisms. Whether pH-mediated activation of TRP channels is also involved in other areas of the brain and nervous system and in humans remains to be determined, but these results suggest that targeting TRPA1 channels may be therapeutically beneficial in treating stroke patients (see Saab and Nave).

N. B. Hamilton, K. Kolodziejczyk, E. Kougioumtzidou, D. Attwell, Proton-gated Ca2+-permeable TRP channels damage myelin in conditions mimicking ischaemia. Nature 529, 523–527 (2016). [PubMed]

A. S. Saab, K.-A. Nave, A mechanism for myelin injury. Nature 529, 474–475 (2016). [PubMed]

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