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J. Biol. Chem., Vol. 280, Issue 51, 42290-42299, December 23, 2005

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Death-associated Protein Kinase Is Activated by Dephosphorylation in Response to Cerebral Ischemia^*

Mehrdad Shamloo1, Liza Soriano, Tadeusz Wieloch, Karoly Nikolich, Roman Urfer, and Donna Oksenberg

From the AGY Therapeutics, Inc., South San Francisco, California 94080 and Laboratory for Experimental Brain Research, Wallenberg Neuroscience Center, Lund University, BMCA13, 22184 Lund, Sweden

Death-associated protein kinase (DAPK) is a calcium calmodulin-regulated serine/threonine protein kinase involved in ischemic neuronal death. In situ hybridization experiments show that DAPK mRNA expression is up-regulated in brain following a global ischemic insult and down-regulated in ischemic tissues after focal ischemia. DAPK is inactive in normal brain tissues, where it is found in its phosphorylated state and becomes rapidly and persistently dephosphorylated and activated in response to ischemia in vivo. A similar dephosphorylation pattern is detected in primary cortical neurons subjected to oxygen glucose deprivation or N-methyl-D-aspartate (NMDA)-induced toxicity. Both a calcineurin inhibitor, FK506, and a selective NMDA receptor antagonist, MK-801, inhibit the dephosphorylation of DAPK after in vitro ischemia. This indicates that DAPK could be activated by NMDA receptor-mediated calcium flux, activation of calcineurin, and subsequent DAPK dephosphorylation. Moreover, concomitantly to dephosphorylation, DAPK is proteolytically processed by cathepsin after ischemia. Furthermore, a selective DAPK inhibitor is neuroprotective in both in vitro and in vivo ischemic models. These results indicate that DAPK plays a key role in mediating ischemic neuronal injury.

Received for publication, May 27, 2005 , and in revised form, September 14, 2005.

^* 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.

¹ To whom correspondence should be addressed: AGY Therapeutics, Inc. 270 E. Grand Ave., South San Francisco, CA 94080. Tel.: 650-228-1151; Fax: 650-615-4544; E-mail: mshamloo{at}agyinc.com.

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