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The Journal of Neuroscience, December 12, 2007, 27(50):13781-13792; doi:10.1523/JNEUROSCI.2042-07.2007
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Cellular/Molecular
Cx43 Hemichannels and Gap Junction Channels in Astrocytes Are Regulated Oppositely by Proinflammatory Cytokines Released from Activated Microglia
Mauricio A. Retamal,1 Nicolas Froger,2,3 Nicolas Palacios-Prado,1 Pascal Ezan,2,3 Pablo J. Sáez,1 Juan C. Sáez,1 andChristian Giaume2,3 1Departamento de Ciencias Fisiológicas, Pontificia Universidad Católica de Chile, Santiago 6513492, Chile, 2Institut National de la Santé et de la Recherche Médicale, U840, 75005 Paris, France, and 3Collège de France, 75005 Paris, France
Correspondence should be addressed to either of the following: Dr. Christian Giaume, Institut National de la Santé et de la Recherche Médicale U840, Collège de France, 11 place Marcelin Berthelot, 75005 Paris, France, Email: christian.giaume{at}college-de-france.fr; or Dr. Juan C. Sáez, Departamento de Ciencias Fisiológicas, Universidad Católica de Chile, Alameda 340, Santiago 6513492, Chile, E-mail: Email: jsaez{at}bio.puc.cl
Astrocytes have a role in maintaining normal neuronal functions, some of which depend on connexins, protein subunits of gap junction channels and hemichannels. Under inflammatory conditions, microglia release cytokines, including interleukin-1β and tumor necrosis factor-
, that reduce intercellular communication via gap junctions. Now, we demonstrate that either conditioned medium harvested from activated microglia or a mixture of these two cytokines enhances the cellular exchange with the extracellular milieu via Cx43 hemichannels. These changes in membrane permeability were not detected in astrocytes cultured from Cx43 knock-out mice and were abrogated by connexin hemichannel blockers, including La3+, mimetic peptides, and niflumic acid. Both the reduction in gap junctional communication and the increase in membrane permeability were mediated by a p38 mitogen-activated protein kinase-dependent pathway. However, the increase in membrane permeability, but not the gap junction inhibition, was rapidly reversed by the sulfhydryl reducing agent dithiothreitol, indicating that final regulatory mechanisms are different. Treatment with proinflammatory cytokines reduced the total and cell surface Cx43 levels, suggesting that the increase in membrane permeability was attributable to an increase in hemichannels activity. Indeed, unitary events of
220 pS corresponding to Cx43 hemichannels were much more frequent in astrocytes treated with microglia conditioned medium than under control conditions. Finally, the effect of cytokines enhanced the uptake and reduced the intercellular diffusion of glucose, which might explain changes in the metabolic status of astrocytes under inflammatory conditions. Accordingly, this opposite regulation may affect glucose trafficking and certainly will modify the metabolic status of astrocytes involved in brain inflammation.
Key words: glial cells; connexin; inflammation; nitric oxide; gap junction; glucose
Received May 4, 2007; revised Sept. 21, 2007; accepted Sept. 24, 2007.
Correspondence should be addressed to either of the following: Dr. Christian Giaume, Institut National de la Santé et de la Recherche Médicale U840, Collège de France, 11 place Marcelin Berthelot, 75005 Paris, France, Email: christian.giaume{at}college-de-france.fr; or Dr. Juan C. Sáez, Departamento de Ciencias Fisiológicas, Universidad Católica de Chile, Alameda 340, Santiago 6513492, Chile, E-mail: Email: jsaez{at}bio.puc.cl
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