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Calmodulin Kinase IV –dependent CREB activation is required for neuroprotection via NMDA receptor‐ PSD 95 disruption
Author(s) -
Bell Karen F. S.,
Bent Russell J.,
MeeseTamuri Saira,
Ali Alicia,
Forder Joan P.,
Aarts Michelle M.
Publication year - 2013
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12176
Subject(s) - creb , neuroprotection , excitotoxicity , nmda receptor , kinase , phosphorylation , protein kinase a , microbiology and biotechnology , chemistry , glutamate receptor , pharmacology , biology , receptor , biochemistry , transcription factor , gene
NMDA ‐type glutamate receptors mediate both trophic and excitotoxic signalling in CNS neurons. We have previously shown that blocking NMDAR ‐ post‐synaptic density‐95 ( PSD 95) interactions provides significant protection from excitotoxicity and in vivo ischaemia; however, the mechanism of neuroprotection is unclear. Here, we report that blocking PSD ‐95 interactions with the Tat‐ NR 2B9c peptide enhances a Ca 2 + ‐dependent protective pathway converging on cAMP Response Element binding protein ( CREB ) activation. We provide evidence that Tat‐ NR 2B9c neuroprotection from oxygen glucose deprivation and NMDA toxicity occurs in parallel with the activation of calmodulin kinase signalling and is dependent on a sustained phosphorylation of the CREB transcription factor and its activator Ca MKIV . Tat‐ NR 2B9c‐dependent neuroprotection and CREB phosphorylation are blocked by coapplication of CaM kinase ( KN 93 and STO ‐609) or CREB ( KG ‐501) inhibitors, and by si RNA knockdown of Ca MKIV . These results are mirrored in vivo in a rat model of permanent focal ischaemia. Tat‐ NR 2B9c application significantly reduces infarct size and causes a selective and sustained elevation in Ca MKIV phosphorylation; effects which are blocked by coadministration of KN 93. Thus, calcium‐dependent nuclear signalling via Ca MKIV and CREB is critical for neuroprotection via NMDAR ‐ PSD 95 blockade, both in vitro and in vivo . This study highlights the importance of maintaining neuronal function following ischaemic injury. Future stroke research should target neurotrophic and pro‐survival signal pathways in the development of novel neuroprotective strategies.