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

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

Abstract

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

Substances

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