About this item:

221 Views | 313 Downloads

Author Notes:

Corresponding Author: Uhtaek Oh; Sensory Research Center, Creative Research Initiatives, College of Pharmacy, Seoul National University, Seoul, South Korea Email: utoh@snu.ac.kr

JL recorded channel currents and carried out structural modeling; JJ carried out the Ca2+ overlay and SPR assays

JW, BL, YJ, and YDY worked on mutagenesis

MHT, HC, DJY, and HwC carried out current recordings

SHP and BWH worked on structural modeling

SH and JY worked on SPR assay

HCH planned and wrote the manuscript

and OU planned, supervised experiments, and wrote the manuscript.

The authors declare that they have no conflict of interest.


Research Funding:

This research was supported by a grant from the National Research Foundation of Korea (no. 20110018358), a grant from BK21+ program of Ministry of Education of Korea, and NIH grants GM60448 and EY114852 (HCH)


  • Science & Technology
  • Life Sciences & Biomedicine
  • Physiology
  • Anoctamin 1
  • Anoctamin 2
  • Calcium
  • Activation
  • Helix
  • Structure

Two helices in the third intracellular loop determine anoctamin 1 (TMEM16A) activation by calcium

Show all authors Show less authors


Journal Title:

Pflügers Archiv European Journal of Physiology


Volume 467, Number 8


, Pages 1677-1687

Type of Work:

Article | Final Publisher PDF


Anoctamin 1 (ANO1)/TMEM16A is a Cl<sup>−</sup> channel activated by intracellular Ca<sup>2+</sup> mediating numerous physiological functions. However, little is known of the ANO1 activation mechanism by Ca<sup>2+</sup>. Here, we demonstrate that two helices, “reference” and “Ca<sup>2+</sup> sensor” helices in the third intracellular loop face each other with opposite charges. The two helices interact directly in a Ca<sup>2+</sup>-dependent manner. Positively and negatively charged residues in the two helices are essential for Ca<sup>2+</sup>-dependent activation because neutralization of these charges change the Ca<sup>2+</sup> sensitivity. We now predict that the Ca<sup>2+</sup> sensor helix attaches to the reference helix in the resting state, and as intracellular Ca<sup>2+</sup> rises, Ca<sup>2+</sup> acts on the sensor helix, which repels it from the reference helix. This Ca<sup>2+</sup>-dependent push-pull conformational change would be a key electromechanical movement for gating the ANO1 channel. Because chemical activation of ANO1 is viewed as an alternative means of rescuing cystic fibrosis, understanding its gating mechanism would be useful in developing novel treatments for cystic fibrosis.

Copyright information:

© 2014, The Author(s).

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