The ion channel TRPM8 is a direct target of the immunosuppressant rapamycin in primary sensory neurons

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
出处
期刊:British Journal of Pharmacology [Wiley]
标识
DOI:10.1111/bph.16402
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.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
过客匆匆完成签到,获得积分10
刚刚
今天很美味完成签到 ,获得积分10
1秒前
1秒前
2秒前
李健应助KingYH采纳,获得10
3秒前
ai zs发布了新的文献求助10
7秒前
好好好完成签到 ,获得积分10
8秒前
wanci应助过客匆匆采纳,获得10
8秒前
呼噜噜完成签到,获得积分20
8秒前
情怀应助weiyu_u采纳,获得30
10秒前
kchrisuzad完成签到,获得积分10
11秒前
tuotuo完成签到,获得积分10
12秒前
忧子忘完成签到,获得积分10
13秒前
14秒前
14秒前
15秒前
朴素的凉面完成签到,获得积分10
16秒前
yiqifan完成签到,获得积分0
16秒前
ccjjpp1243完成签到 ,获得积分10
17秒前
大气夜南发布了新的文献求助10
18秒前
维生素发布了新的文献求助10
18秒前
英俊的铭应助袁寒烟采纳,获得10
18秒前
19秒前
张涵完成签到,获得积分10
19秒前
卟茨卟茨完成签到,获得积分10
20秒前
KingYH发布了新的文献求助10
20秒前
琉风完成签到,获得积分20
23秒前
24秒前
平常映雁完成签到,获得积分10
25秒前
25秒前
xzx完成签到 ,获得积分10
26秒前
老肖完成签到,获得积分10
26秒前
sumugeng完成签到,获得积分10
26秒前
28秒前
如意完成签到,获得积分10
29秒前
KingYH完成签到,获得积分10
29秒前
31秒前
周冯雪完成签到 ,获得积分10
33秒前
34秒前
廖天佑完成签到,获得积分10
34秒前
高分求助中
The Oxford Handbook of Social Cognition (Second Edition, 2024) 1050
Kinetics of the Esterification Between 2-[(4-hydroxybutoxy)carbonyl] Benzoic Acid with 1,4-Butanediol: Tetrabutyl Orthotitanate as Catalyst 1000
The Young builders of New china : the visit of the delegation of the WFDY to the Chinese People's Republic 1000
юрские динозавры восточного забайкалья 800
English Wealden Fossils 700
Handbook of Qualitative Cross-Cultural Research Methods 600
Chen Hansheng: China’s Last Romantic Revolutionary 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3139996
求助须知:如何正确求助?哪些是违规求助? 2790894
关于积分的说明 7796961
捐赠科研通 2447258
什么是DOI,文献DOI怎么找? 1301779
科研通“疑难数据库(出版商)”最低求助积分说明 626340
版权声明 601194