Ultraviolet light and photosensitising agents activate TRPA1 via generation of oxidative stress

Abstract

TRPA1, a Ca 2+-permeable cation channel that is expressed in sensory neurones, is involved in the perception of chemical irritants and mechanical hyperalgesia. TRPA1 is activated by either covalent or reversible binding of various chemical compounds, including allylisothiocyanate or acrolein, and is further sensitised by increases in the intracellular Ca 2+ concentration. We here demonstrate that TRPA1 confers a sensitivity towards near ultraviolet (UVA) light, which rapidly causes Ca 2+ entry. In electrophysiological recordings in whole cell and inside out modes, exposure to UVA light activated typical TRPA1 currents in a wavelength-dependent and membrane-delimited manner. In the presence of the photosensitising agents acridine orange (100 nM) or hypericin (10 nM), the sensitivity of light-induced TRPA1 activation was increased and extended towards the visible spectrum. Since extracellular application of hydrogen peroxide mimicked the effect of UVA irradiation and since dithiothreitol partly reversed the activation by UVA exposure, we conclude that reactive oxygen species may mediate the light-induced activation of TRPA1. Accordingly, hydrogen peroxide induced a TRPA1 activation with a membrane-delimited mode of action that was attenuated by dithiothreitol. Intracellular but not extracellular application of FeSO 4, which catalyses the formation of highly reactive hydroxyl radicals potentiated the hydrogen peroxide-stimulated TRPA1 activation. We conclude that, via generation of reactive oxygen species, light-induced TRPA1 activation provides an additional mode of activation, which renders TRPA1 a likely molecular candidate in processes leading to painful or burning sensations during photodynamic therapy or upon local application of hydrogen peroxide.