Role of Akt and Ca2+ on cell permeabilization via connexin43 hemichannels induced by metabolic inhibition

Biochim Biophys Acta. 2015 Jul;1852(7):1268-77. doi: 10.1016/j.bbadis.2015.03.004. Epub 2015 Mar 14.


Connexin hemichannels are regulated under physiological and pathological conditions. Metabolic inhibition, a model of ischemia, promotes surface hemichannel activation associated, in part, with increased surface hemichannel levels, but little is known about its underlying mechanism. Here, we investigated the role of Akt on the connexin43 hemichannel's response induced by metabolic inhibition. In HeLa cells stably transfected with rat connexin43 fused to EGFP (HeLa43 cells), metabolic inhibition induced a transient Akt activation necessary to increase the amount of surface connexin43. The increase in levels of surface connexin43 was also found to depend on an intracellular Ca2+ signal increase that was partially mediated by Akt activation. However, the metabolic inhibition-induced Akt activation was not significantly affected by intracellular Ca2+ chelation. The Akt-dependent increase in connexin43 hemichannel activity in HeLa43 cells also occurred after oxygen-glucose deprivation, another ischemia-like condition, and in cultured cortical astrocytes (endogenous connexin43 expression system) under metabolic inhibition. Since opening of hemichannels has been shown to accelerate cell death, inhibition of Akt-dependent phosphorylation of connexin43 hemichannels could reduce cell death induced by ischemia/reperfusion.

Keywords: Akt activation; Intracellular Ca(2+); Oxygen-glucose deprivation; Surface hemichannels.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Astrocytes / metabolism
  • Calcium / metabolism*
  • Cell Hypoxia
  • Cell Membrane Permeability
  • Cells, Cultured
  • Connexin 43 / metabolism*
  • Glucose / deficiency*
  • HeLa Cells
  • Humans
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats
  • Rats, Sprague-Dawley


  • Connexin 43
  • Proto-Oncogene Proteins c-akt
  • Glucose
  • Calcium