title: Role of Akt and Ca2+ on cell permeabilization via connexin43 hemichannels induced by metabolic inhibition.
abstract: 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.
authors.affiliation: Advanced Center for Chronic Diseases (ACCDIS) & Centro Estudios Moleculares de la Célula (CMEC), Facultad Ciencias Químicas y Farmacéuticas & Facultad Medicina, Universidad de Chile, Santiago, Chile; Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile. Electronic address: danielasalas@gmail.com.
authors.forename: Daniela
authors.initials: D
authors.lastname: Salas
authors.affiliation: Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Carlos
authors.initials: C
authors.lastname: Puebla
authors.affiliation: Translational Research Program, Human Biology and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Lampe
authors.affiliation: Advanced Center for Chronic Diseases (ACCDIS) & Centro Estudios Moleculares de la Célula (CMEC), Facultad Ciencias Químicas y Farmacéuticas & Facultad Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Sergio
authors.initials: S
authors.lastname: Lavandero
authors.affiliation: Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile; Instituto Milenio, Centro Interdisciplinario de Neurociencias de Valparaíso, Valparaíso, Chile. Electronic address: jsaez@bio.puc.cl.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Sáez
mesh_terms: D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D015687:Cell Hypoxia; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism*; D005947:Glucose / Q000172:deficiency*; D006367:HeLa Cells; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018031:Connexin 43; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose; D002118:Calcium
keywords: Akt activation; Intracellular Ca(2+); Oxygen-glucose deprivation; Surface hemichannels