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An electrostatic mechanism for Ca(2+)-mediated regulation of gap junction channels.
Bennett, Brad C; Purdy, Michael D; Baker, Kent A; Acharya, Chayan; McIntire, William E; Stevens, Raymond C; Zhang, Qinghai; Harris, Andrew L; Abagyan, Ruben; Yeager, Mark.
Afiliación
  • Bennett BC; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
  • Purdy MD; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
  • Baker KA; Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
  • Acharya C; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, California 92093, USA.
  • McIntire WE; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
  • Stevens RC; Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.
  • Zhang Q; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
  • Harris AL; Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Newark, New Jersey 07103, USA.
  • Abagyan R; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, California 92093, USA.
  • Yeager M; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
Nat Commun ; 7: 8770, 2016 Jan 12.
Article en En | MEDLINE | ID: mdl-26753910
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Calcio / Conexinas / Electricidad Estática Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Calcio / Conexinas / Electricidad Estática Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido