The capsaicin and mustard oil receptors TRPV1 and TRPA1, respectively, are highly expressed in polymodal nociceptors, ubiquitous thin nerve fibers that can evoke pain and induce “neurogenic inflammation” by neuropeptide secretion. Reversible oxidation of intracellular cysteine residues of these channel proteins causes activation and sensitization to adequate stimuli. The ion channel activity can be assessed in cultured sensory neurons, transfected cell lines, and in artificial lipid bilayers, using patch-clamp recording, calcium microfluorimetry, and indirectly by single-fiber recording and enzyme immunoassay measurement of stimulated neuropeptide (CGRP) release from isolated organ preparations. Strikingly, we found that ordinary blue light (405 nm) activates human TRPA1 and evokes pain in white human skin. This results from the ubiquitous presence of the heme precursor protoporphyrin IX (Pp IX) that acts as a chromophore to produce singlet oxygen under illumination. The ensuing oxidation of the TRP channels accounts for the pain and skin damage porphyria patients suffer upon sunlight exposure and for the painful side effects of photodynamic therapy of cutaneous cancers. However, another genetic syndrome of extreme and painful photosensitivity, Smith-Lemli-Opitz disease, results from the accumulation of the cholesterol and vitamin D3 precursor 7-dehydrocholesterol (7-DHC) which is neither excited by visible or UVA light nor produces singlet oxygen to oxidize the TRPs. Nonetheless, we could demonstrate that 7-DHC is a particularly sensitive target of light (350-430 nm)-induced oxidation which produces oxysterols known to generate reactive oxygen species and lipid peroxides that activate both TRP channels. The severe abdominal pain attacks of porphyria patients remain to be elucidated.
TRPV1; TRPA1; porphyria; photodermatitis; chromophore; singlet oxygen; 7dehydrocholesterol; CGRP.
Babes A, Sauer SK, Moparthi L, Kichko TI, Neacsu C, Namer B, Filipovic M, Zygmunt PM, Reeh PW, Fischer MJ. 2016 Photosensitization in Porphyrias and Photodynamic Therapy Involves TRPA1 and TRPV1. J Neurosci. 36: 5264-5278. Babes A, Ciotu CI, Hoffmann T, Kichko TI, Selescu T, Neacsu C, Sauer SK, Reeh PW, Fischer MJM. 2017 Photosensitization of TRPA1 and TRPV1 by 7-dehydrocholesterol: implications for the Smith-Lemli-Opitz syndrome. Pain. 158: 2475-2486.