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

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

SUBMITTER: Le SC 

PROVIDER: S-EPMC6704070 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature