title: Sustained TRPA1 activation in vivo.
abstract: Transient receptor potential A1 (TRPA1) is a calcium permeable non-selective cation channel that is selectively localized to peptidergic C-fibres in the pain pathway. TRPA1 is highly conserved across the animal kingdom and it is able to detect a wide range of potentially toxic environmental chemicals. An unusual mechanism of TRPA1 activation was recently elucidated in which reactive agonists bind covalently to cysteines and lysine in the intracellular N-terminus. Despite a covalent activation mechanism, only transient TRPA1 activation is seen in the maintained presence of reactive agonists in whole-cell patch clamp experiments. I suggest that previous patch clamp studies are performed under conditions that do not fully mimic all aspects of TRPA1 activation. Here, I argue that compelling evidence exists for sustained TRPA1 activation in several chronic (neuropathic) pain-related pathophysiological conditions in vivo. I discuss briefly putative mechanisms that are likely to contribute to and maintain sustained TRPA1 agonist levels through increased production and/or decreased metabolism and inactivation. Chronic pain can be understood as a false alarm evoked by sustained and increased levels of endogenous TRPA1 agonists in various pathophysiological conditions.
authors.affiliation: In Vitro Pharmacology, Orion Pharma Orion Corporation, Turku, Finland. ari-pekka.koivisto@orionpharma.com
authors.forename: A
authors.initials: A
authors.lastname: Koivisto
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D059350:Chronic Pain / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D023421:Models, Animal; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050052:TRPC Cation Channels; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C480976:Trpa1 protein, rat; D002118:Calcium