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

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Le, SC; Jia, Z; Chen, J; Yang, H

Published Date

  • August 21, 2019

Published In

Volume / Issue

  • 10 / 1

Start / End Page

  • 3769 -

PubMed ID

  • 31434906

Pubmed Central ID

  • 31434906

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-019-11784-8

Language

  • eng

Conference Location

  • England