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J. Biol. Chem., Vol. 280, Issue 16, 16208-16218, April 22, 2005

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Oxygen-sensitive -Opioid Receptor-regulated Survival and Death Signals

NOVEL INSIGHTS INTO NEURONAL PRECONDITIONING AND PROTECTION^*

Ming-Chieh Ma, Hong Qian, Farshid Ghassemi, Peng Zhao, and Ying Xia

From the Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06520

The detrimental effect of severe hypoxia (SH) on neurons can be mitigated by hypoxic preconditioning (HPC), but the molecular mechanisms involved remain unclear, and an understanding of these may provide novel solutions for hypoxic/ischemic disorders (e.g. stroke). Here, we show that the -opioid receptor (DOR), an oxygen-sensitive membrane protein, mediates the HPC protection through specific signaling pathways. Although SH caused a decrease in DOR expression and neuronal injury, HPC induced an increase in DOR mRNA and protein levels and reversed the reduction in levels of the endogenous DOR peptide, leucine enkephalin, normally seen during SH, thus protecting the neurons from SH insult. The HPC-induced protection could be blocked by DOR antagonists. The DOR-mediated HPC protection depended on an increase in ERK and Bcl 2 activity, which counteracted the SH-induced increase in p38 MAPK activities and cytochrome c release. The cross-talk between ERK and p38 MAPKs displays a "yinyang" antagonism under the control of the DOR-G protein-protein kinase C pathway. Our findings demonstrate a novel mechanism of HPC neuroprotection (i.e. the intracellular up-regulation of DOR-regulated survival signals).

Received for publication, July 16, 2004 , and in revised form, January 25, 2005.

^* This study was supported by National Institutes of Health Grants HD-34852 and AT-01094 (to Y. X.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Pediatrics, Yale School of Medicine, 333 Cedar St., LMP 3107, New Haven, CT 06520. Tel.: 203-785-6101; Fax: 203-785-6337; E-mail: ying.xia{at}yale.edu.

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