The FASEB Journal • Research Communication The thermosensitive TRPV3 channel contributes to rapid wound healing in oral epithelia Reona Aijima,* ,†,‡ Bing Wang,* Tomoka Takao,* Hiroshi Mihara, § Makiko Kashio, § Yasuyoshi Ohsaki,* Jing-Qi Zhang,* Atsuko Mizuno, { Makoto Suzuki, { Yoshio Yamashita, † Sadahiko Masuko, ‡ Masaaki Goto, † Makoto Tominaga, § and Mizuho A. Kido* ,1 *Department of Molecular Cell Biology and Oral Anatomy, Graduate School of Dental Science, Kyushu University, Fukuoka, Japan; † Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Saga University, Saga, Japan; ‡ Division of Histology and Neuroanatomy, Department of Anatomy and Physiology, Faculty of Medicine, Saga University, Saga, Japan; § Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Japan; and { Department of Pharmacology, Jichi Medical University, Shimotsuke, Japan ABSTRACT The oral cavity provides an entrance to the alimentary tract to serve as a protective barrier against harmful environmental stimuli. The oral mucosa is susceptible to injury because of its location; nonethe- less, it has faster wound healing than the skin and less scar formation. However, the molecular pathways regu- lating this wound healing are unclear. Here, we show that transient receptor potential vanilloid 3 (TRPV3), a ther- mosensitive Ca 2+ -permeable channel, is more highly expressed in murine oral epithelia than in the skin by quantitative RT-PCR. We found that temperatures above 33°C activated TRPV3 and promoted oral epithelial cell proliferation. The proliferation rate in the oral epithelia of TRPV3 knockout (TRPV3KO) mice was less than that of wild-type (WT) mice. We investigated the contribution of TRPV3 to wound healing using a molar tooth extraction model and found that oralwound closure was delayed in TRPV3KO mice compared with that in WT mice. TRPV3 mRNA was up-regulated in wounded tissues, suggesting that TRPV3 may contribute to oral wound repair. We identified TRPV3 as an essen- tial receptor in heat-induced oral epithelia proliferation and wound healing. Our findings suggest that TRPV3 activation could be a potential therapeutic target for wound healing in skin and oral mucosa.—Aijima, R., Wang, B., Takao, T., Mihara, H., Kashio, M., Ohsaki, Y., Zhang, J.-Q., Mizuno, A., Suzuki, M., Yamashita, Y., Masuko, S., Goto, M., Tominaga, M., Kido, M. A. The thermosensitive TRPV3 channel contributes to rapid wound healing in oral epithelia. FASEB J. 29, 000–000 (2015). www.fasebj.org Key Words: TRP channels • ambient temperature • oral mucosa • wound repair THE ORAL MUCOSA HAS a highly specialized epithelium that performs essential protective functions against diverse changes, such as chemical, thermal, or mechanical stimuli, in the oral environment. The oral cavity is also the site for sentient responses (1, 2). The oral epithelium is a moist lining membrane in the oral cavity and consists of a stratified squamous epithelium and underlying connec- tive tissues similar to the skin. Although it is continuous with the skin, the oral epithelium is more susceptible to injury because it is exposed to more extensive stimuli than the skin. However, wound repair of the oral mucosa is faster than the skin and recovers with less scar formation (3, 4). Although components in the saliva or a rich vascular supply may contribute to this rapid wound healing (4–6), the molecular mechanisms regulating oral mucosa wound repair are still largely unknown. Transient receptor potential (TRP) channels are a family of Ca 2+ -permeable nonselective cation channels that are responsive to a broad range of environmental stimuli such as temperature, tonicity, or pain (7–9). Among the 28 different mammalian TRP channels, transient receptor poten- tial vanilloid 3 (TRPV3) is uniquely expressed predominantly in keratinocytes and is activated by innocuous warm temper- atures above 33°C and natural herbs such as oregano or thyme (10–14). Furthermore, it has been shown that skin keratinocytes detect ambient temperatures by TRPV3 and TRPV4 activation (10, 11, 15), and this temperature information is transmitted to the neighboring nerves (16). Although the oral cavity is exposed to a more dynamic range of temperatures and is more sensitive than the skin, the mechanisms by which these temperatures are recognized have not been elucidated. Accumulating evidence has demonstrated that TRPV3 in skin keratinocytes contributes to physiologic skin Abbreviations: 2-APB, 2-aminoethoxydiphenyl borate; [Ca 2+ ] i , intracellular Ca 2+ concentration; CK14, cytokeratin 14; EdU, 5-ethynyl-29 -deoxyuridine; EGFR, epidermal growth factor receptor; GSK, GSK1016790A; FBS, fetal bovine serum; KO, knockout; LN, laminin-111; P, postnatal day; p-EGFR, phosphorylated epidermal growth factor receptor; PFA, paraformaldehyde; qPCR, quantitative PCR; RuR, ruthenium red; TRP, transient receptor potential; TRPV3, transient receptor potential vanilloid 3; WT, wild-type 1 Correspondence: Department of Molecular Cell Biology and Oral Anatomy, Graduate School of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812- 8582, Japan. E-mail: kido@dent.kyushu-u.ac.jp doi: 10.1096/fj.14-251314 This article includes supplemental data. Please visit http:// www.fasebj.org to obtain this information. 0892-6638/15/0029-0001 © FASEB 1 The FASEB Journal article fj.14-251314. Published online October 28, 2014. Vol., No. , pp:, September, 2016 The FASEB Journal . 54.226.8.15 to IP www.fasebj.org Downloaded from Vol., No. , pp:, September, 2016 The FASEB Journal . 54.226.8.15 to IP www.fasebj.org Downloaded from Vol., No. , pp:, September, 2016 The FASEB Journal . 54.226.8.15 to IP www.fasebj.org Downloaded from Vol., No. , pp:, September, 2016 The FASEB Journal . 54.226.8.15 to IP www.fasebj.org Downloaded from Vol., No. , pp:, September, 2016 The FASEB Journal . 54.226.8.15 to IP www.fasebj.org Downloaded from Vol., No. , pp:, September, 2016 The FASEB Journal . 54.226.8.15 to IP www.fasebj.org Downloaded from Vol., No. , pp:, September, 2016 The FASEB Journal . 54.226.8.15 to IP www.fasebj.org Downloaded from