An electrostatic mechanism for Ca(2+)-mediated regulation of gap junction channels

Nat Commun. 2016 Jan 12;7:8770. doi: 10.1038/ncomms9770.


Gap junction channels mediate intercellular signalling that is crucial in tissue development, homeostasis and pathologic states such as cardiac arrhythmias, cancer and trauma. To explore the mechanism by which Ca(2+) blocks intercellular communication during tissue injury, we determined the X-ray crystal structures of the human Cx26 gap junction channel with and without bound Ca(2+). The two structures were nearly identical, ruling out both a large-scale structural change and a local steric constriction of the pore. Ca(2+) coordination sites reside at the interfaces between adjacent subunits, near the entrance to the extracellular gap, where local, side chain conformational rearrangements enable Ca(2+)chelation. Computational analysis revealed that Ca(2+)-binding generates a positive electrostatic barrier that substantially inhibits permeation of cations such as K(+) into the pore. Our results provide structural evidence for a unique mechanism of channel regulation: ionic conduction block via an electrostatic barrier rather than steric occlusion of the channel pore.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Connexin 26
  • Connexins / chemistry
  • Connexins / metabolism*
  • Crystallization
  • Crystallography, X-Ray
  • Humans
  • Molecular Dynamics Simulation
  • Protein Structure, Tertiary
  • Sf9 Cells
  • Spodoptera
  • Static Electricity*
  • Synchrotrons


  • Connexins
  • GJB2 protein, human
  • Connexin 26
  • Calcium