Death-associated protein kinase is activated by dephosphorylation in response to cerebral ischemia.
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.
Shamloo
Mehrdad
M
AGY Therapeutics, Inc., South San Francisco, California 94080, USA. mshamloo@agyinc.com
Soriano
Liza
L
Wieloch
Tadeusz
T
Nikolich
Karoly
K
Urfer
Roman
R
Oksenberg
Donna
D
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002545:Brain Ischemia / Q000201:enzymology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D064550:Death-Associated Protein Kinases; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D008297:Male; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000494:pharmacology
D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D016291:Dizocilpine Maleate; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D005947:Glucose; D010100:Oxygen; D016559:Tacrolimus