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

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

Author information

1
Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
2
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
3
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, California 92093, USA.
4
Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
5
Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.
6
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
7
Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Newark, New Jersey 07103, USA.
8
Center for Membrane Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
9
Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
10
Department of Medicine, Division of Cardiovascular Medicine, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.

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.

PMID:
26753910
PMCID:
PMC4730032
DOI:
10.1038/ncomms9770
[Indexed for MEDLINE]
Free PMC Article

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