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

Son C. Le, Zhiguang Jia, Jianhan Chen and Huanghe Yang ()
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Son C. Le: Duke University Medical Center
Zhiguang Jia: University of Massachusetts
Jianhan Chen: University of Massachusetts
Huanghe Yang: Duke University Medical Center

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11784-8

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