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

Author

Listed:
  • Brad C. Bennett

    (University of Virginia School of Medicine
    Present address: Department of Biology and Environmental Sciences, Samford University, Birmingham, Alabama 35209, USA.)

  • 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
    The Scripps Research Institute
    Center for Membrane Biology, University of Virginia School of Medicine
    Cardiovascular Research Center, University of Virginia School of Medicine)

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.

Suggested Citation

  • Brad C. Bennett & Michael D. Purdy & Kent A. Baker & Chayan Acharya & William E. McIntire & Raymond C. Stevens & Qinghai Zhang & Andrew L. Harris & Ruben Abagyan & Mark Yeager, 2016. "An electrostatic mechanism for Ca2+-mediated regulation of gap junction channels," Nature Communications, Nature, vol. 7(1), pages 1-12, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms9770
    DOI: 10.1038/ncomms9770
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    Cited by:

    1. Hyuk-Joon Lee & Hyung Jin Cha & Hyeongseop Jeong & Seu-Na Lee & Chang-Won Lee & Minsoo Kim & Jejoong Yoo & Jae-Sung Woo, 2023. "Conformational changes in the human Cx43/GJA1 gap junction channel visualized using cryo-EM," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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