TRPA1 acts as a cold sensor in vitro and in vivo

doi:10.1073/pnas.0808487106

TRPA1 acts as a cold sensor in vitro and in vivo

^aLaboratory of Ion Channel Research, Division of Physiology, Department of Molecular Cell Biology, Campus Gasthuisberg O&N1, Katholieke Universiteit Leuven, Herestraat 49 bus 802, B-3000 Leuven, Belgium;
^bDepartment of Urology, University Hospitals Gasthuisberg, Katholieke Universiteit Leuven, Herestraat 49 bus 802, B-3000 Leuven, Belgium; and
^cNeurobiology, Harvard Medical School, 220 Longwood Avenue, Goldenson 443, Boston, MA 02115

Edited by Lutz Birnbaumer, National Institutes of Health, Research Triangle Park, NC, and approved December 3, 2008 (received for review August 27, 2008)

Abstract

TRPA1 functions as an excitatory ionotropic receptor in sensory neurons. It was originally described as a noxious cold-activated channel, but its cold sensitivity has been disputed in later studies, and the contribution of TRPA1 to thermosensing is currently a matter of strong debate. Here, we provide several lines of evidence to establish that TRPA1 acts as a cold sensor in vitro and in vivo. First, we demonstrate that heterologously expressed TRPA1 is activated by cold in a Ca²⁺-independent and Ca²⁺ store-independent manner; temperature-dependent gating of TRPA1 is mechanistically analogous to that of other temperature-sensitive TRP channels, and it is preserved after treatment with the TRPA1 agonist mustard oil. Second, we identify and characterize a specific subset of cold-sensitive trigeminal ganglion neurons that is absent in TRPA1-deficient mice. Finally, cold plate and tail-flick experiments reveal TRPA1-dependent, cold-induced nociceptive behavior in mice. We conclude that TRPA1 acts as a major sensor for noxious cold.

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Footnotes

¹To whom correspondence should be addressed. E-mail: thomas.voets{at}med.kuleuven.be
Author contributions: Y.K., K.T., R.V., B.N., and T.V. designed research; Y.K., K.T., W.E., A.J., R.V., and T.V. performed research; K.Y.K. contributed new reagents/analytic tools; Y.K., K.T., and T.V. analyzed data; and Y.K. and T.V. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0808487106/DCSupplemental.