Why the study?
High-resolution TMEM16A structures have failed to reveal an activated state with an unobstructed permeation pathway even with saturating Ca2+, leaving the molecular mechanisms of gating and regulation poorly understood.
Specific binding of PIP2 to TMEM16A leads to spontaneous opening of the permeation pathway in the Ca2+-bound state, providing a molecular basis for understanding TMEM16A channel activation.
Mechanistic insight into TMEM16A gating; leaves open therapeutic translation to human cardiovascular disease.
TMEM16A is a widely expressed Ca 2+ -activated Cl - channel that regulates crucial physiological functions including fluid secretion, neuronal excitability, and smooth muscle contraction. There is a critical need to understand the molecular mechanisms of TMEM16A gating and regulation. However, high-resolution TMEM16A structures have failed to reveal an activated state with unobstructed permeation pathway even with saturating Ca 2+ . This has been attributed to the requirement of PIP 2 for preventing TMEM16A desensitization. Here, we show that specific binding PIP 2 to TMEM16A can lead to spontaneous opening of the permeation pathway in the Ca 2+ -bound state. The predicted activated state is highly consistent with a wide range of mutagenesis and functional data. It yields a maximal Cl - conductance of ~1 pS, similar to experimental estimates, and recapitulates the selectivity of larger SCN - over Cl - . The resulting molecular mechanism of activation provides a basis for understanding the interplay of multiple signals in controlling TMEM16A channel function.
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Jia et al. (2020) studied this question.
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