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Author Notes:

Correspondence: H. Criss Hartzell. criss.hartzell@emory.edu

The authors declare that they have no conflict of interest.


Research Funding:

Research in the authors’ lab is funded by grants AR067786, GM60448, and EY114852 from the National Institutes of Health and a Grant from the Muscular Dystrophy Association.

JMW was supported by NIH Training Grant 5T32GM008367.


  • Anoctamin
  • TMEM16
  • Chloride channel
  • Phospholipid scrambling
  • Protein-lipid interactions
  • Calcium

A Pore Idea: the ion conduction pathway of TMEM16/ANO proteins is composed partly of lipid


Journal Title:

Pflügers Archiv - European Journal of Physiology


Volume 468, Number 3


, Pages 455-473

Type of Work:

Article | Final Publisher PDF


Since their first descriptions, ion channels have been conceived as proteinaceous conduits that facilitate the passage of ionic cargo between segregated environments. This concept is reinforced by crystallographic structures of cation channels depicting ion conductance pathways completely lined by protein. Although lipids are sometimes present in fenestrations near the pore or may be involved in channel gating, there is little or no evidence that lipids inhabit the ion conduction pathway. Indeed, the presence of lipid acyl chains in the conductance pathway would curse the design of the channel’s aqueous pore. Here, we make a speculative proposal that anion channels in the TMEM16/ANO superfamily have ion conductance pathways composed partly of lipids. Our reasoning is based on the idea that TMEM16 ion channels evolved from a kind of lipid transporter that scrambles lipids between leaflets of the membrane bilayer and the modeled structural similarity between TMEM16 lipid scramblases and TMEM16 anion channels. This novel view of the TMEM16 pore offers explanation for the biophysical and pharmacological oddness of TMEM16A. We build upon the recent X-ray structure of nhTMEM16 and develop models of both TMEM16 ion channels and lipid scramblases to bolster our proposal. It is our hope that this model of the TMEM16 pore will foster innovative investigation into TMEM16 function.

Copyright information:

© The Author(s) 2016

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).

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