Yoshioka Takeshi, Imura Kinichi, Asakawa Makoto, Suzuki Minoru, Oshima Itsuki, Hirasawa Tsutomu, Sakata Tsuneaki, Horikawa Tatsuya, Arimura Akinori
Shionogi Discovery Research Laboratories, Shionogi and Co. Ltd, Osaka, Japan.
J Invest Dermatol. 2009 Mar;129(3):714-22. doi: 10.1038/jid.2008.245. Epub 2008 Aug 28.
We reported that the Gly573Ser substitution in transient receptor potential vanilloid 3 (TRPV3) led to increased ion channel activity in keratinocytes and caused spontaneous hairlessness in DS-Nh mice. DS-Nh mice also develop allergic and pruritic dermatitis. As the hairless and dermatitis phenotypes were both inherited in an autosomal dominant fashion and could not be segregated from each other, we speculated that TRPV3(Gly573Ser) might be responsible for the dermatitis. Here, we constructed TRPV3(Gly573Ser) transgenic mice, with a putative promoter sequence in the 5' region of TRPV3, to investigate the involvement of TRPV3 in the development of specific types of dermatitis. These transgenic mice spontaneously developed dermatitis, whereas wild-type mice did not display this phenotype when maintained under the same conditions. Histological and serological analyses were carried out to better understand the clinical features of TRPV3(Gly573Ser) transgenic mice. A physiological study revealed that TRPV3(Gly573Ser) induced a higher nerve growth factor response to heat. Finally, C57BL-Nh mice were used to investigate the penetrance of the TRPV3(Gly573Ser) gene for dermatitis. Interestingly, C57BL-Nh mice developed spontaneous scratching behavior, separately from the development of dermatitis. We propose that TRPV3(Gly573Ser) is a cause of pruritus and/or dermatitis associated with scratching, and suggest that TRPV3 may represent a therapeutic target in pruritic dermatitis.
我们报道，瞬时受体电位香草酸亚型3（TRPV3）中的Gly573Ser替代导致角质形成细胞中离子通道活性增加，并在DS-Nh小鼠中引起自发性脱毛。DS-Nh小鼠还会发生过敏性和瘙痒性皮炎。由于无毛和皮炎表型均以常染色体显性方式遗传，且无法相互分离，我们推测TRPV3（Gly573Ser）可能是皮炎的病因。在此，我们构建了TRPV3（Gly573Ser）转基因小鼠，其在TRPV3的5'区域具有假定的启动子序列，以研究TRPV3在特定类型皮炎发展中的作用。这些转基因小鼠自发发生皮炎，而野生型小鼠在相同条件下饲养时未表现出该表型。进行了组织学和血清学分析，以更好地了解TRPV3（Gly573Ser）转基因小鼠的临床特征。一项生理学研究表明，TRPV3（Gly573Ser）对热诱导出更高的神经生长因子反应。最后，使用C57BL-Nh小鼠研究TRPV3（Gly573Ser）基因对皮炎的外显率。有趣的是，C57BL-Nh小鼠出现了自发抓挠行为，与皮炎的发展无关。我们提出TRPV3（Gly573Ser）是与抓挠相关的瘙痒和/或皮炎的病因，并表明TRPV3可能是瘙痒性皮炎的治疗靶点。
