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Research Article

Fast structural responses of gap junction membrane domains to AB5 toxins

Irina V. Majoul, Liang Gao, Eric Betzig, Daria Onichtchouk, Eugenia Butkevich, Yuri Kozlov, Feliksas Bukauskas, Michael V. L. Bennett, Jennifer Lippincott-Schwartz, and Rainer Duden
  1. aInstitute of Biology, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany;
  2. bJanelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147;
  3. cCenter for Biological Signaling Studies, Albert Ludwigs University, 79104 Freiburg, Germany;
  4. dDrittes Physikalisches Institut, Biophysik, Georg-August-Universität, 37077 Göttingen, Germany;
  5. eV.A. Engelhardt Institute for Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia;
  6. fDominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461; and
  7. gEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892

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PNAS first published October 16, 2013; https://doi.org/10.1073/pnas.1315850110
Irina V. Majoul
aInstitute of Biology, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany;
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  • For correspondence: irina.majoul@bio.uni-luebeck.de lippincj@mail.nih.gov duden@bio.uni-luebeck.de
Liang Gao
bJanelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147;
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Eric Betzig
bJanelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147;
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Daria Onichtchouk
cCenter for Biological Signaling Studies, Albert Ludwigs University, 79104 Freiburg, Germany;
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Eugenia Butkevich
dDrittes Physikalisches Institut, Biophysik, Georg-August-Universität, 37077 Göttingen, Germany;
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Yuri Kozlov
eV.A. Engelhardt Institute for Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia;
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Feliksas Bukauskas
fDominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461; and
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Michael V. L. Bennett
fDominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461; and
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Jennifer Lippincott-Schwartz
gEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
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  • For correspondence: irina.majoul@bio.uni-luebeck.de lippincj@mail.nih.gov duden@bio.uni-luebeck.de
Rainer Duden
aInstitute of Biology, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany;
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  • For correspondence: irina.majoul@bio.uni-luebeck.de lippincj@mail.nih.gov duden@bio.uni-luebeck.de
  1. Contributed by Jennifer Lippincott-Schwartz, September 9, 2013 (sent for review June 20, 2013)

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Significance

We used 3D Bessel beam plane illumination and spinning disk microscopy to reveal fast structural changes in the architecture of gap junctions (GJs). Previously, GJ plaques were considered relatively stable structures. We demonstrate extremely rapid remodeling of proteins and lipids within GJ plaques in response to bacterial toxin exposure. Connexin channels within GJ plaques undergo dramatic rearrangements that lead to increased connexin packing and lipid reorganization. These changes likely reflect lipid-phase separation events in the biological membrane. Toxin-induced connexin reorganization depends on lipids and is little modified by membrane–cytoskeletal interactions. We suggest that fast GJ changes upon toxin exposure reveal an early-response system of cells and that GJ plaques are much more dynamic structures than previously recognized.

Abstract

Gap junctions (GJs) represent connexin-rich membrane domains that connect interiors of adjoining cells in mammalian tissues. How fast GJs can respond to bacterial pathogens has not been known previously. Using Bessel beam plane illumination and confocal spinning disk microscopy, we found fast (∼500 ms) formation of connexin-depleted regions (CDRs) inside GJ plaques between cells exposed to AB5 toxins. CDR formation appears as a fast redistribution of connexin channels within GJ plaques with minor changes in outline or geometry. CDR formation does not depend on membrane trafficking or submembrane cytoskeleton and has no effect on GJ conductance. However, CDR responses depend on membrane lipids, can be modified by cholesterol-clustering agents and extracellular K+ ion concentration, and influence cAMP signaling. The CDR response of GJ plaques to bacterial toxins is a phenomenon observed for all tested connexin isoforms. Through signaling, the CDR response may enable cells to sense exposure to AB5 toxins. CDR formation may reflect lipid-phase separation events in the biological membrane of the GJ plaque, leading to increased connexin packing and lipid reorganization. Our data demonstrate very fast dynamics (in the millisecond-to-second range) within GJ plaques, which previously were considered to be relatively stable, long-lived structures.

  • membrane traffic
  • connexin actin
  • cell–cell junctions
  • cholesterol

Footnotes

  • ↵1To whom correspondence may be addressed. E-mail: irina.majoul{at}bio.uni-luebeck.de, lippincj{at}mail.nih.gov, or duden{at}bio.uni-luebeck.de.
  • Author contributions: I.V.M., F.B., and R.D. designed research; I.V.M., L.G., F.B., and R.D. performed research; I.V.M., L.G., E. Betzig, D.O., E. Butkevich, Y.K., F.B., and J.L.-S. contributed new reagents/analytic tools; I.V.M., L.G., E. Betzig, D.O., E. Butkevich, Y.K., F.B., M.V.L.B., J.L.-S., and R.D. analyzed data; and I.V.M., D.O., F.B., M.V.L.B., J.L.-S., and R.D. wrote the paper.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1315850110/-/DCSupplemental.

Freely available online through the PNAS open access option.

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Structural responses of gap junctions to AB5 toxin
Irina V. Majoul, Liang Gao, Eric Betzig, Daria Onichtchouk, Eugenia Butkevich, Yuri Kozlov, Feliksas Bukauskas, Michael V. L. Bennett, Jennifer Lippincott-Schwartz, Rainer Duden
Proceedings of the National Academy of Sciences Oct 2013, 201315850; DOI: 10.1073/pnas.1315850110

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Structural responses of gap junctions to AB5 toxin
Irina V. Majoul, Liang Gao, Eric Betzig, Daria Onichtchouk, Eugenia Butkevich, Yuri Kozlov, Feliksas Bukauskas, Michael V. L. Bennett, Jennifer Lippincott-Schwartz, Rainer Duden
Proceedings of the National Academy of Sciences Oct 2013, 201315850; DOI: 10.1073/pnas.1315850110
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