Huang Susan M, Lee Hyosang, Chung Man-Kyo, Park Una, Yu Yin Yin, Bradshaw Heather B, Coulombe Pierre A, Walker J Michael, Caterina Michael J
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21025, USA.
J Neurosci. 2008 Dec 17;28(51):13727-37. doi: 10.1523/JNEUROSCI.5741-07.2008.
The ability to sense changes in the environment is essential for survival because it permits responses such as withdrawal from noxious stimuli and regulation of body temperature. Keratinocytes, which occupy much of the skin epidermis, are situated at the interface between the external environment and the body's internal milieu, and have long been appreciated for their barrier function against external insults. The recent discovery of temperature-sensitive transient receptor potential vanilloid (TRPV) ion channels in keratinocytes has raised the possibility that these cells also actively participate in acute temperature and pain sensation. To address this notion, we generated and characterized transgenic mice that overexpress TRPV3 in epidermal keratinocytes under the control of the keratin 14 promoter. Compared with wild-type controls, keratinocytes overexpressing TRPV3 exhibited larger currents as well as augmented prostaglandin E(2) (PGE(2)) release in response to two TRPV3 agonists, 2-aminoethoxydiphenyl borate (2APB) and heat. Thermal selection behavior and heat-evoked withdrawal behavior of naive mice overexpressing TRPV3 were not consistently altered. Upon selective pharmacological inhibition of TRPV1 with JNJ-17203212 [corrected], however, the keratinocyte-specific TRPV3 transgenic mice showed increased escape responses to noxious heat relative to their wild-type littermates. Coadministration of the cyclooxygenase inhibitor, ibuprofen, with the TRPV1 antagonist decreased inflammatory thermal hyperalgesia in transgenic but not wild-type animals. Our results reveal a previously undescribed mechanism for keratinocyte participation in thermal pain transduction through keratinocyte TRPV3 ion channels and the intercellular messenger PGE(2).
感知环境变化的能力对于生存至关重要，因为它能引发诸如躲避有害刺激和调节体温等反应。角质形成细胞占据了大部分皮肤表皮，位于外部环境与身体内部环境的界面处，长期以来因其对外部损伤的屏障功能而受到重视。最近在角质形成细胞中发现了温度敏感的瞬时受体电位香草酸（TRPV）离子通道，这增加了这些细胞也积极参与急性温度和疼痛感知的可能性。为了验证这一观点，我们构建并鉴定了在角蛋白14启动子控制下在表皮角质形成细胞中过表达TRPV3的转基因小鼠。与野生型对照相比，过表达TRPV3的角质形成细胞对两种TRPV3激动剂2 - 氨基乙氧基二苯硼酸（2APB）和热刺激表现出更大的电流以及增强的前列腺素E2（PGE2）释放。过表达TRPV3的未处理小鼠的热选择行为和热诱发的躲避行为并没有持续改变。然而，在用JNJ - 17203212 [校正后]选择性药理抑制TRPV1后，角质形成细胞特异性TRPV3转基因小鼠相对于其野生型同窝小鼠对有害热刺激的逃避反应增加。环氧化酶抑制剂布洛芬与TRPV1拮抗剂共同给药可减轻转基因动物而非野生型动物的炎性热痛觉过敏。我们的结果揭示了角质形成细胞通过角质形成细胞TRPV3离子通道和细胞间信使PGE2参与热痛转导的一种先前未描述的机制。
