An electrostatic mechanism for Ca2+-mediated regulation of gap junction channels

Brad C. Bennett, Michael D. Purdy, Kent A. Baker, Chayan Acharya, William E. McIntire, Raymond C. Stevens, Qinghai Zhang, Andrew L. Harris, Ruben Abagyan and Mark Yeager ()
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Brad C. Bennett: University of Virginia School of Medicine
Michael D. Purdy: University of Virginia School of Medicine
Kent A. Baker: The Scripps Research Institute
Chayan Acharya: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego
William E. McIntire: University of Virginia School of Medicine
Raymond C. Stevens: Bridge Institute, University of Southern California
Qinghai Zhang: The Scripps Research Institute
Andrew L. Harris: Physiology and Neuroscience, Rutgers New Jersey Medical School
Ruben Abagyan: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego
Mark Yeager: University of Virginia School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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 Ca2+ blocks intercellular communication during tissue injury, we determined the X-ray crystal structures of the human Cx26 gap junction channel with and without bound Ca2+. The two structures were nearly identical, ruling out both a large-scale structural change and a local steric constriction of the pore. Ca2+ coordination sites reside at the interfaces between adjacent subunits, near the entrance to the extracellular gap, where local, side chain conformational rearrangements enable Ca2+chelation. Computational analysis revealed that Ca2+-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.

Date: 2016
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DOI: 10.1038/ncomms9770

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