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The Journal of Neuroscience, March 5, 2008, 28(10):2485-2494; doi:10.1523/JNEUROSCI.5369-07.2008

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Cellular/Molecular
Transient Receptor Potential A1 Is a Sensory Receptor for Multiple Products of Oxidative Stress

David A. Andersson, Clive Gentry, Sian Moss, and Stuart Bevan

Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, United Kingdom

Correspondence should be addressed to David A. Andersson, Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, UK. Email: david.andersson{at}kcl.ac.uk

Transient receptor potential A1 (TRPA1) is expressed in a subset of nociceptive sensory neurons where it acts as a sensor for environmental irritants, including acrolein, and some pungent plant ingredients such as allyl isothiocyanate and cinnamaldehyde. These exogenous compounds activate TRPA1 by covalent modification of cysteine residues. We have used electrophysiological methods and measurements of intracellular calcium concentration ([Ca²⁺]_i) to show that TRPA1 is activated by several classes of endogenous thiol-reactive molecules. TRPA1 was activated by hydrogen peroxide (H₂O₂; EC₅₀, 230 µM), by endogenously occurring alkenyl aldehydes (EC₅₀: 4-hydroxynonenal 19.9 µM, 4-oxo-nonenal 1.9 µM, 4-hydroxyhexenal 38.9 µM) and by the cyclopentenone prostaglandin, 15-deoxy-^12,14-prostaglandin J₂ (15d-PGJ₂, EC₅₀: 5.6 µM). The effect of H₂O₂ was reversed by treatment with dithiothreitol indicating that H₂O₂ acts by promoting the formation of disulfide bonds whereas the actions of the alkenyl aldehydes and 15d-PGJ₂ were not reversed, suggesting that these agents form Michael adducts. H₂O₂ and the naturally occurring alkenyl aldehydes and 15d-PGJ₂ acted on a subset of isolated rat and mouse sensory neurons [25% of rat dorsal root ganglion (DRG) and 50% of nodose ganglion neurons] to evoke a depolarizing inward current and an increase in [Ca²⁺]_i in TRPA1 expressing neurons. The abilities of H₂O₂, alkenyl aldehydes and 15d-PGJ₂ to raise [Ca²⁺]_i in mouse DRG neurons were greatly reduced in neurons from trpa1^–/– mice. Furthermore, intraplantar injection of either H₂O₂ or 15d-PGJ2 evoked a nocifensive/pain response in wild-type mice, but not in trpa1^–/– mice. These data demonstrate that multiple agents produced during episodes of oxidative stress can activate TRPA1 expressed in sensory neurons.

Key words: TRPA1; DRG; hydrogen peroxide; 4-hydroxynonenal; 15d-PGJ₂; oxidative stress

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Received July 16, 2007; revised Jan. 18, 2008; accepted Jan. 20, 2008.

Correspondence should be addressed to David A. Andersson, Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, UK. Email: david.andersson{at}kcl.ac.uk

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				T. E. Taylor-Clark, M. A. McAlexander, C. Nassenstein, S. A. Sheardown, S. Wilson, J. Thornton, M. J. Carr, and B. J. Undem Relative contributions of TRPA1 and TRPV1 channels in the activation of vagal bronchopulmonary C-fibres by the endogenous autacoid 4-oxononenal J. Physiol., July 15, 2008; 586(14): 3447 - 3459. [Abstract] [Full Text] [PDF]

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