Heterotypic gap junction channels as voltage-sensitive valves for intercellular signaling

Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14855-60. doi: 10.1073/pnas.0901923106. Epub 2009 Aug 24.


Gap junction (GJ) channels assembled from connexin (Cx) proteins provide a structural basis for direct electrical and metabolic cell-cell communication. By combining fluorescence imaging and dual whole-cell voltage clamp methods, we demonstrate that in response to transjunctional voltage (Vj) Cx43/Cx45 heterotypic GJs exhibit both Vj-gating and dye transfer asymmetries. The later is affected by ionophoresis of charged fluorescent dyes and voltage-dependent gating. We demonstrate that small differences in resting (holding) potentials of communicating cells can fully block (at relative negativity on Cx45 side) or enhance (at relative positivity on Cx45 side) dye transfer. Similarly, series of high frequency Vj pulses resembling bursts of action potentials (APs) can fully block or increase the transjunctional flux (Jj) of dye depending on whether pulses are generated in the cell expressing Cx43 or Cx45, respectively. Asymmetry of Jj-Vj dependence is enhanced or reduced when ionophoresis and Vj-gating act synergistically or antagonistically, whereas single channel permeability (Pgamma) remains unaffected. This modulation of intercellular signaling by Vj can play a crucial role in many aspects of intercellular communication in the adult, in embryonic development, and in tissue regeneration.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Communication*
  • Connexin 43 / genetics
  • Connexin 43 / metabolism*
  • Connexins / genetics
  • Connexins / metabolism*
  • Electrophysiological Phenomena
  • Gap Junctions / metabolism*
  • HeLa Cells
  • Humans
  • Patch-Clamp Techniques
  • Protein Binding
  • Signal Transduction*


  • Connexin 43
  • Connexins
  • connexin 45