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Acta Physiol (Oxf). 2012 Feb;204(2):248-54. doi: 10.1111/j.1748-1716.2011.02318.x. Epub 2011 May 28.

Sustained TRPA1 activation in vivo.

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1
In Vitro Pharmacology, Orion Pharma Orion Corporation, Turku, Finland. ari-pekka.koivisto@orionpharma.com

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.

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