TRPA1 modulates mechanotransduction in cutaneous sensory neurons

Transient receptor potential ankyrin 1 (TRPAI) 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 TRPAl to cold and mechanotransduction in cutaneous primary afferent terminals, we used the ex vivo skin-nerve preparation from Trpal ^+/+, Trpal ^+/-, and Trpal ^-/- adult mouse littermates. Cutaneous fibers from TRPAl-deficient mice showed no deficits in acute cold sensitivity, but they displayed striking deficits in mechanical response properties. C-fiber nociceptors from Trpal ^-/- mice exhibited action potential firing rates 50% lower than those in wild-type C-fibers across a wide range of force intensities. Aδ-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. TRPAl protein and mRNA expression was assessed in DRG neurons and cutaneous innervation by using Trpal in situ hybridization, an antibody for TRPAl, and an antibody for placental alkaline phosphatase (PLAP) in mice in which PLAP was substituted for Trpal. DRG neurons of all sizes expressed Trpal mRNA or PLAP immunoreactivity. TRPAl 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 TRPAl message and protein. We propose that TRPAl 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.