Specific PIP₂ binding promotes calcium activation of TMEM16A chloride channels

TMEM16A is a widely expressed Ca²⁺-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 an unobstructed permeation pathway even with saturating Ca²⁺. This has been attributed to the requirement of PIP₂ for preventing TMEM16A desensitization. Here, atomistic simulations show that specific binding of PIP₂ to TMEM16A can lead to spontaneous opening of the permeation pathway in the Ca²⁺-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.