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The Journal of Neuroscience, April 15, 2009, 29(15):4808-4819; doi:10.1523/JNEUROSCI.5380-08.2009

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Cellular/Molecular
TRPA1 Modulates Mechanotransduction in Cutaneous Sensory Neurons

Kelvin Y. Kwan,^1,2 * Joshua M. Glazer,^3 * David P. Corey,^1,2 Frank L. Rice,^4,5 and Cheryl L. Stucky³

¹Department of Neurobiology and ²Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, ³Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, ⁴Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York 12054, and ⁵Integrated Tissue Dynamics LLC, Renssalear, New York 12144

Correspondence should be addressed to Dr. Cheryl L. Stucky, Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. Email: cstucky{at}mcw.edu

Transient receptor potential ankyrin 1 (TRPA1) is expressed by nociceptive neurons of the dorsal root ganglia (DRGs) and trigeminal ganglia, but its roles in cold and mechanotransduction are controversial. To determine the contribution of TRPA1 to cold and mechanotransduction in cutaneous primary afferent terminals, we used the ex vivo skin–nerve preparation from Trpa1^+/+, Trpa1^+/–, and Trpa1^–/– adult mouse littermates. Cutaneous fibers from TRPA1-deficient mice showed no deficits in acute cold sensitivity, but they displayed striking deficits in mechanical response properties. C-fiber nociceptors from Trpa1^–/– mice exhibited action potential firing rates 50% lower than those in wild-type C-fibers across a wide range of force intensities. A-fiber mechanonociceptors also had reduced firing, but only at high intensity forces (>100 mN). Surprisingly, the firing rates of low-threshold Aβ and D-hair mechanoreceptive fibers were also altered. TRPA1 protein and mRNA expression was assessed in DRG neurons and cutaneous innervation by using Trpa1 in situ hybridization, an antibody for TRPA1, and an antibody for placental alkaline phosphatase (PLAP) in mice in which PLAP was substituted for Trpa1. DRG neurons of all sizes expressed Trpa1 mRNA or PLAP immunoreactivity. TRPA1 or PLAP immunolabeling was detected not only on many thin-caliber axons and intraepidermal endings but also on many large-caliber axons as well as lanceolate and Meissner endings. Epidermal and hair follicle keratinocytes also express TRPA1 message and protein. We propose that TRPA1 modulates mechanotransduction via a cell-autonomous mechanism in nociceptor terminals and possibly through a modulatory role in keratinocytes, which may interact with sensory terminals to modify their mechanical firing properties.

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Received Nov. 7, 2008; revised Feb. 11, 2009; accepted Feb. 25, 2009.

Correspondence should be addressed to Dr. Cheryl L. Stucky, Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. Email: cstucky{at}mcw.edu

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