Conformational changes and CO2-induced channel gating in connexin26

Structure. 2022 May 5;30(5):697-706.e4. doi: 10.1016/j.str.2022.02.010. Epub 2022 Mar 10.


Connexins form large-pore channels that function either as dodecameric gap junctions or hexameric hemichannels to allow the regulated movement of small molecules and ions across cell membranes. Opening or closing of the channels is controlled by a variety of stimuli, and dysregulation leads to multiple diseases. An increase in the partial pressure of carbon dioxide (PCO2) has been shown to cause connexin26 (Cx26) gap junctions to close. Here, we use cryoelectron microscopy (cryo-EM) to determine the structure of human Cx26 gap junctions under increasing levels of PCO2. We show a correlation between the level of PCO2 and the size of the aperture of the pore, governed by the N-terminal helices that line the pore. This indicates that CO2 alone is sufficient to cause conformational changes in the protein. Analysis of the conformational states shows that movements at the N terminus are linked to both subunit rotation and flexing of the transmembrane helices.

Keywords: KID syndrome; channel gating; connexins; cryo-EM; membrane protein; regulation by CO(2).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbon Dioxide* / metabolism
  • Cell Membrane / metabolism
  • Connexin 26
  • Connexins* / chemistry
  • Connexins* / metabolism
  • Cryoelectron Microscopy
  • Gap Junctions / metabolism
  • Humans


  • Connexins
  • GJB2 protein, human
  • Connexin 26
  • Carbon Dioxide