title: Photosensitization in Porphyrias and Photodynamic Therapy Involves TRPA1 and TRPV1.
abstract: Photosensitization, an exaggerated sensitivity to harmless light, occurs genetically in rare diseases, such as porphyrias, and in photodynamic therapy where short-term toxicity is intended. A common feature is the experience of pain from bright light. In human subjects, skin exposure to 405 nm light induced moderate pain, which was intensified by pretreatment with aminolevulinic acid. In heterologous expression systems and cultured sensory neurons, exposure to blue light activated TRPA1 and, to a lesser extent, TRPV1 channels in the absence of additional photosensitization. Pretreatment with aminolevulinic acid or with protoporphyrin IX dramatically increased the light sensitivity of both TRPA1 and TRPV1 via generation of reactive oxygen species. Artificial lipid bilayers equipped with purified human TRPA1 showed substantial single-channel activity only in the presence of protoporphyrin IX and blue light. Photosensitivity and photosensitization could be demonstrated in freshly isolated mouse tissues and led to TRP channel-dependent release of proinflammatory neuropeptides upon illumination. With antagonists in clinical development, these findings may help to alleviate pain during photodynamic therapy and also allow for disease modification in porphyria patients.
  
  
  
  Cutaneous porphyria patients suffer from burning pain upon exposure to sunlight and other patients undergoing photodynamic therapy experience similar pain, which can limit the therapeutic efforts. This study elucidates the underlying molecular transduction mechanism and identifies potential targets of therapy. Ultraviolet and blue light generates singlet oxygen, which oxidizes and activates the ion channels TRPA1 and TRPV1. The disease and the therapeutic options could be reproduced in models ranging from isolated ion channels to human subjects, applying protoporphyrin IX or its precursor aminolevulinic acid. There is an unmet medical need, and our results suggest a therapeutic use of the pertinent antagonists in clinical development.
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany, Department of Anatomy, Physiology and Biophysics, Faculty of Biology, University of Bucharest, 050095 Bucharest, Romania.
authors.forename: Alexandru
authors.initials: A
authors.lastname: Babes
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Susanne K
authors.initials: SK
authors.lastname: Sauer
authors.affiliation: Department of Biochemistry and Structural Biology, Center for Molecular Protein Science, Lund University, SE-221 00 Lund, Sweden.
authors.forename: Lavanya
authors.initials: L
authors.lastname: Moparthi
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Tatjana I
authors.identifier: 0000-0003-1330-0849
authors.initials: TI
authors.lastname: Kichko
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Cristian
authors.initials: C
authors.lastname: Neacsu
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Namer
authors.affiliation: Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nuremberg, 91058 Erlangen, Germany, and.
authors.forename: Milos
authors.initials: M
authors.lastname: Filipovic
authors.affiliation: Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, SE-221 85 Lund, Sweden.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Zygmunt
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany, peter.reeh@fau.de.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Reeh
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Michael J M
authors.identifier: 0000-0002-3811-7066
authors.initials: MJ
authors.lastname: Fischer
mesh_terms: D000622:Aminolevulinic Acid / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000378:metabolism; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology*; D011164:Porphyrias / Q000378:metabolism* / Q000628:therapy; D011524:Protoporphyrins / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000528:radiation effects; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000378:metabolism*; D050051:Transient Receptor Potential Channels / Q000378:metabolism*
chemical_list: D009479:Neuropeptides; D017319:Photosensitizing Agents; D011524:Protoporphyrins; D017382:Reactive Oxygen Species; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX
keywords: aminolaevulinic acid; pain; protoporphyrin IX