TRPM8型
热感受器
瞬时受体电位通道
PI3K/AKT/mTOR通路
雷帕霉素的作用靶点
药理学
西罗莫司
化学
生物
细胞生物学
信号转导
TRPV1型
神经科学
受体
感觉系统
生物化学
作者
José Miguel Arcas,Khalid Oudaha,Alejandro González,Jorge Fernández‐Trillo,Francisco Andrés Peralta,Júlia Castro‐Marsal,Seyma Poyraz,Francisco J. Taberner,Salvador Sala,Elvira de la Peña,Ana Gomis,Félix Viana
摘要
Background and Purpose The mechanistic target of rapamycin (mTOR) signalling pathway is a key regulator of cell growth and metabolism. Its deregulation is implicated in several diseases. The macrolide rapamycin, a specific inhibitor of mTOR, has immunosuppressive, anti‐inflammatory and antiproliferative properties. Recently, we identified tacrolimus, another macrolide immunosuppressant, as a novel activator of TRPM8 ion channels, involved in cold temperature sensing, thermoregulation, tearing and cold pain. We hypothesized that rapamycin may also have agonist activity on TRPM8 channels. Experimental Approach Using calcium imaging and electrophysiology in transfected HEK293 cells and wildtype or Trpm8 KO mouse DRG neurons, we characterized rapamycin’s effects on TRPM8 channels. We also examined the effects of rapamycin on tearing in mice. Key Results Micromolar concentrations of rapamycin activated rat and mouse TRPM8 channels directly and potentiated cold‐evoked responses, effects also observed in human TRPM8 channels. In cultured mouse DRG neurons, rapamycin increased intracellular calcium levels almost exclusively in cold‐sensitive neurons. Responses were markedly decreased in Trpm8 KO mice or by TRPM8 channel antagonists. Cutaneous cold thermoreceptor endings were also activated by rapamycin. Topical application of rapamycin to the eye surface evokes tearing in mice by a TRPM8‐dependent mechanism. Conclusion and Implications These results identify TRPM8 cationic channels in sensory neurons as novel molecular targets of the immunosuppressant rapamycin. These findings may help explain some of its therapeutic effects after topical application to the skin and the eye surface. Moreover, rapamycin could be used as an experimental tool in the clinic to explore cold thermoreceptors.
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