期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2023572118
关键词
TMEM16A; calcium signalling; pharmacology; CaCC
资金
- British Heart Foundation (BHF) DPhil studentship [FS/17/45/33102]
- Wellcome (OXION) DPhil studentship [102161/Z/13/Z]
- Clarendon Scholarship
- BHF [PG/19/8/34168]
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/T007664/1]
- Wellcome
- Wellcome [208361/Z/17/Z]
- BBSRC [BB/P01948X/1, BB/R002517/1, BB/S003339/1]
- Medical Research Council (MRC) [MR/S009213/1]
- Engineering and Physical Sciences Research Council (EPSRC) [EP/L000253/1]
- BBSRC [BB/P01948X/1, BB/T007664/1, BB/S003339/1, BB/R002517/1] Funding Source: UKRI
- MRC [MR/S009213/1] Funding Source: UKRI
Research has found that TMEM16A channels are sensitive to the extracellular modulator A9C in the presence of intracellular Ca2+, but insensitive when intracellular Ca2+ is omitted. This conclusion highlights a critical site for pharmacological intervention and reveals an aspect of Ca2+ gating in the TMEM16A channel.
TMEM16A Ca2+-activated chloride channels are involved in multiple cellular functions and are proposed targets for diseases such as hypertension, stroke, and cystic fibrosis. This therapeutic endeavor, however, suffers from paucity of selective and potent modulators. Here, exploiting a synthetic small molecule with a biphasic effect on the TMEM16A channel, anthracene-9-carboxylic acid (A9C), we shed light on sites of the channel amenable for pharmacological intervention. Mutant channels with the intracellular gate constitutively open were generated. These channels were entirely insensitive to extracellular A9C when intracellular Ca(2+ )was omitted. However, when physiological Ca2+ levels were reestablished, the mutants regained sensitivity to A9C. Thus, intracellular Ca2+ is mandatory for the channel response to an extracellular modulator. The underlying mechanism is a conformational change in the outer pore that enables A9C to enter the pore to reach its binding site. The explanation of this structural rearrangement highlights a critical site for pharmacological intervention and reveals an aspect of Ca2+ gating in the TMEM16A channel.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据