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Increased Connexin 43 Expression as a Potential Mediator of the Neuroprotective Activity of the Corticotropin-Releasing Hormone

Institute of Pathobiochemistry, University Medical Center (R.H., C.B., A.B.C.), Department of Biology, Unit of Molecular Cell Biology (J.T.), Johannes Gutenberg-University, 55099 Mainz, Germany

Address all correspondence and requests for reprints to: A.B. Clement or C. Behl, Institute of Physiological Chemistry and Pathobiochemistry, University Medicine, Johannes Gutenberg-University of Mainz, Duesbergweg 6, 55099 Mainz, Germany. E-mail: clemena{at}uni-mainz.de or cbehl{at}uni-mainz.de.

CRH is a major central stress mediator, but also a potent neuroprotective effector. The mechanisms by which CRH mediates its neuroprotective actions are largely unknown. Here, we describe that the gap junction molecule connexin43 (Cx43) mediates neuroprotective effects of CRH toward experimentally induced oxidative stress. An enhanced gap junction communication has been reported to contribute to neuroprotection after neurotoxic insults. We show that CRH treatment up-regulates Cx43 expression and gap junctional communication in a CRH receptor-dependent manner in IMR32 neuroblastoma cells, primary astrocytes, and organotypic hippocampal slice cultures. MAPKs and protein kinase A-cAMP response element binding protein -coupled pathways are involved in the signaling cascade from CRH to enhanced Cx43 function. Inhibition of CRH-promoted gap junction communication by the gap junction inhibitor carbenoxolone could prevent neuroprotective actions of CRH in cell and tissue culture models suggesting that gap junction molecules are involved in the neuroprotective effects of CRH. The extent of oxidative stress-induced protein carbonylation and cell death inversely correlated with Cx43 protein levels as shown by Cx43 small interfering RNA knockdown experiments. Coculture studies of primary neurons and astrocytes revealed that astrocytic Cx43 likely contributes to the neuroprotective effects of CRH. To our knowledge this is the first description of Cx43 as a potential mediator of the neuroprotective actions of CRH.