Excitotoxic neuroprotection and vulnerability with CaMKII inhibition

Nicole M. Ashpole, Andy Hudmon

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Aberrant calcium signaling is a common feature of ischemia and multiple neurodegenerative diseases. While activation of calcium-calmodulin (CaM)-dependent protein kinase II (CaMKII) is a key event in calcium signaling, its role in excitotoxicity is controversial. Our findings demonstrate neuroprotection in neuronal cultures treated with the small molecule (KN-93) and peptide (tat-AIP and tat-CN21) inhibitors of CaMKII immediately prior to excitotoxic glutamate/glycine insult. Unlike KN-93 which blocks CaMKII activation, but not constitutively active forms of CaMKII, tat-CN21 and tat-AIP significantly reduced excitotoxicity in cultured neurons when applied post-insult. We observed that the neuroprotective effects of tat-CN21 are greatest when applied before the toxic glutamate challenge and diminish with time, with the neuroprotection associated with CaMKII inhibition diminishing back to control 3. h post glutamate insult. Mechanistically, tat-CN21 inhibition of CaMKII resulted in an increase in CaMKII activity and the percentage of soluble αCaMKII observed in neuronal lysates 24. h following glutamate stimulation. To address the impact of prolonged CaMKII inhibition prior to excitotoxic insult, neuronal cultures were treated with CaMKII inhibitors overnight and then subjected to a sub-maximal excitotoxic insult. In this model, CaMKII inhibition prior to insult exacerbated neuronal death, suggesting that a loss of CaMKII enhances neuronal vulnerability to glutamate. Although changes in αCaMKII or NR2B protein levels are not responsible for this enhanced glutamate vulnerability, this process is blocked by the protein translation inhibitor cycloheximide. In total, the neuroprotection afforded by CaMKII inhibition can be seen as neuroprotective immediately surrounding the excitotoxic insult, whereas sustained CaMKII inhibition produced by excitotoxicity leads to neuronal death by enhancing neuronal vulnerability to glutamate.

Original languageEnglish
Pages (from-to)720-730
Number of pages11
JournalMolecular and Cellular Neuroscience
Volume46
Issue number4
DOIs
StatePublished - Apr 2011

Fingerprint

Protein Kinases
Glutamic Acid
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium Signaling
Neuroprotection
Calcium-Calmodulin-Dependent Protein Kinases
Poisons
Protein Biosynthesis
Neuroprotective Agents
Cycloheximide
Protein Kinase Inhibitors
Neurodegenerative Diseases
Glycine
Ischemia
Neurons
Peptides

Keywords

  • Aberrant calcium signaling
  • CaMKII inactivation
  • Cortical neurons
  • Excitotoxicity
  • Ischemia
  • Kinase inhibitors

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Cell Biology

Cite this

Excitotoxic neuroprotection and vulnerability with CaMKII inhibition. / Ashpole, Nicole M.; Hudmon, Andy.

In: Molecular and Cellular Neuroscience, Vol. 46, No. 4, 04.2011, p. 720-730.

Research output: Contribution to journalArticle

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