Recent progress in structural studies on TMEM16A channel
Sai Shi1,2,3, Chunli Pang3, Shuai Guo1,2,3
1State Key Laboratory of Reliability and Intelligence of Electrical Equipment, Hebei University of Technology, Tianjin 300401, China.
Abstract:
The calcium-activated chloride channel, also known as TMEM16A, shows both calcium and membrane potential dependent activation. The channel is expressed broadly and contributes to a variety of physiological processes, and it is expected to be a target for the treatment of diseases such as hypertension, pain, cystic fibrosis and lung cancer. A thorough understanding of the structural characteristics of TMEM16A is important to reveal its physiological and pathological roles. Recent studies have released several Cryo-EM structures of the channel, revealed the structural basis and mechanism of the gating of the channel. This review focused on the understandings of the structural basis and molecular mechanism of the gating and permeation of TMEM16A channel, which will provide important basis for the development of drugs targeting TMEM16A.
Insights
The TMEM16A channel, activated by calcium, is crucial for physiological processes and disease treatment. Recent Cryo-EM structures reveal its gating mechanism, aiding drug development.
Area of Science:
- Molecular biology
- Structural biology
- Biophysics
Background:
- The calcium-activated chloride channel, TMEM16A, plays vital roles in numerous physiological processes.
- TMEM16A is implicated in diseases including hypertension, pain, cystic fibrosis, and lung cancer.
- Understanding TMEM16A structure is key to elucidating its function and pathological involvement.
Purpose of the Study:
- To review the structural basis of TMEM16A gating and permeation.
- To elucidate the molecular mechanisms underlying TMEM16A channel function.
- To provide a foundation for developing TMEM16A-targeting therapeutics.
Main Methods:
- Analysis of recent Cryo-electron microscopy (Cryo-EM) structures of TMEM16A.
- Integration of structural data with functional and biophysical studies.
- Review of literature on TMEM16A gating and permeation mechanisms.
Main Results:
- Cryo-EM studies have provided high-resolution structures of TMEM16A.
- These structures reveal the intricate details of channel gating and ion permeation pathways.
- The structural insights explain the calcium and membrane potential dependency of TMEM16A activation.
Conclusions:
- Structural understanding of TMEM16A is advancing rapidly.
- Elucidating the gating and permeation mechanisms is crucial for understanding TMEM16A's physiological and pathological roles.
- This knowledge is essential for the rational design of drugs targeting TMEM16A for various diseases.
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