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Molecular basis of PIP2-dependent regulation of the Ca2+-activated chloride channel TMEM16A

Author

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  • Son C. Le

    (Duke University Medical Center)

  • Zhiguang Jia

    (University of Massachusetts)

  • Jianhan Chen

    (University of Massachusetts
    University of Massachusetts)

  • Huanghe Yang

    (Duke University Medical Center
    Duke University Medical Center)

Abstract

The calcium-activated chloride channel (CaCC) TMEM16A plays crucial roles in regulating neuronal excitability, smooth muscle contraction, fluid secretion and gut motility. While opening of TMEM16A requires binding of intracellular Ca2+, prolonged Ca2+-dependent activation results in channel desensitization or rundown, the mechanism of which is unclear. Here we show that phosphatidylinositol (4,5)-bisphosphate (PIP2) regulates TMEM16A channel activation and desensitization via binding to a putative binding site at the cytosolic interface of transmembrane segments (TMs) 3–5. We further demonstrate that the ion-conducting pore of TMEM16A is constituted of two functionally distinct modules: a Ca2+-binding module formed by TMs 6–8 and a PIP2-binding regulatory module formed by TMs 3–5, which mediate channel activation and desensitization, respectively. PIP2 dissociation from the regulatory module results in ion-conducting pore collapse and subsequent channel desensitization. Our findings thus provide key insights into the mechanistic understanding of TMEM16 channel gating and lipid-dependent regulation.

Suggested Citation

  • Son C. Le & Zhiguang Jia & Jianhan Chen & Huanghe Yang, 2019. "Molecular basis of PIP2-dependent regulation of the Ca2+-activated chloride channel TMEM16A," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11784-8
    DOI: 10.1038/s41467-019-11784-8
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    Cited by:

    1. Woori Ko & Euna Lee & Jung-Eun Kim & Hyun-Ho Lim & Byung-Chang Suh, 2024. "The plasma membrane inner leaflet PI(4,5)P2 is essential for the activation of proton-activated chloride channels," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Andy K. M. Lam & Sonja Rutz & Raimund Dutzler, 2022. "Inhibition mechanism of the chloride channel TMEM16A by the pore blocker 1PBC," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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