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The Journal of Neuroscience, January 16, 2008, 28(3):681-695; doi:10.1523/JNEUROSCI.3827-07.2008

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Neurobiology of Disease
A Central Role of Connexin 43 in Hypoxic Preconditioning

Jane H.-C. Lin,¹ Nanhong Lou,³ Ning Kang,² Takahiro Takano,³ Furong Hu,¹ Xiaoning Han,³ Qiwu Xu,³ Ditte Lovatt,³ Arnulfo Torres,³ Klaus Willecke,⁴ Jay Yang,⁵ Jian Kang,² and Maiken Nedergaard³

Departments of ¹Pathology and ²Cell Biology, New York Medical College, Valhalla, New York 10595, ³Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642, ⁴Institut fuer Genetik Rheinische Friedrich-Wilhelms-Universitaet, D-53117 Bonn, Germany, and ⁵Division of Neurobiology Research in Anesthesia, Department of Anesthesiology, Columbia University, New York, New York 10032

Correspondence should be addressed to either of the following: Dr. Jane Lin, Department of Pathology, New York Medical College, Valhalla, NY 10595, Email: jane_lin{at}nymc.edu; or Dr. Maiken Nedergaard, Division of Glial Disease and Therapeutics, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, Email: nedergaard{at}urmc.rochester.edu

Preconditioning is an endogenous mechanism in which a nonlethal exposure increases cellular resistance to subsequent additional severe injury. Here we show that connexin 43 (Cx43) plays a key role in protection afforded by preconditioning. Cx43 null mice were insensitive to hypoxic preconditioning, whereas wild-type littermate mice exhibited a significant reduction in infarct volume after occlusion of the middle cerebral artery. In cultures, Cx43-deficient cells responded to preconditioning only after exogenous expression of Cx43, and protection was attenuated by small interference RNA or by channel blockers. Our observations indicate that preconditioning reduced degradation of Cx43, resulting in a marked increase in the number of plasma membrane Cx43 hemichannels. Consequently, efflux of ATP through hemichannels led to accumulation of its catabolic product adenosine, a potent neuroprotective agent. Thus, adaptive modulation of Cx43 can offset environmental stress by adenosine-mediated elevation of cellular resistance.

Key words: gap junction; astrocytes; hemichannels; stroke; adenosine; GFAP

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Received Aug. 21, 2007; revised Nov. 26, 2007; accepted Nov. 27, 2007.

Correspondence should be addressed to either of the following: Dr. Jane Lin, Department of Pathology, New York Medical College, Valhalla, NY 10595, Email: jane_lin{at}nymc.edu; or Dr. Maiken Nedergaard, Division of Glial Disease and Therapeutics, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, Email: nedergaard{at}urmc.rochester.edu

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