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Ischemia-induced neuronal damage: a role for calcium/calmodulin-dependent protein kinase II
M N Waxham1, J C Grotta, A J Silva
1Department of Neurobiology and Anatomy, University of Texas Medical School at Houston 77225, USA.
Abstract:
Calcium/calmodulin-dependent protein kinase II (CaM-kinase) is a central enzyme in regulating neuronal processes. Imbalances in the activity and distribution of this enzyme have been reported following in vivo ischemia, and sustained decreases in activity correlate with subsequent neuronal death. In this report, mice that had been rendered deficient in the alpha subunit of CaM-kinase using gene knock-out technology were utilized to determine whether this enzyme is causally related to ischemic damage. Using a focal model of cerebral ischemia, we showed that homozygous knock-out mice lacking the alpha subunit exhibited an infarct volume almost twice that of wild-type litter mates. Heterozygous mice exhibited slightly less damage following ischemia than did homozygous mice, but infarct volumes remained significantly larger than those of wild-type litter mates. We conclude that reduced amounts of the alpha subunit of CaM-kinase predisposes neurons to increased damage following ischemia and that any perturbation that decreases the amount or activity of the enzyme will produce enhanced susceptibility to neuronal damage.
Insights
Mice lacking the alpha subunit of Calcium/calmodulin-dependent protein kinase II (CaM-kinase) showed significantly increased brain damage after stroke. Reduced CaM-kinase alpha subunit levels predispose neurons to greater ischemic injury.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Calcium/calmodulin-dependent protein kinase II (CaM-kinase) is crucial for neuronal function.
- Altered CaM-kinase activity is linked to neuronal death after ischemia.
- The role of CaM-kinase alpha subunit in ischemic brain damage requires clarification.
Purpose of the Study:
- To investigate the causal relationship between CaM-kinase alpha subunit deficiency and ischemic brain damage.
- To determine if reduced CaM-kinase alpha subunit levels increase susceptibility to stroke injury.
Main Methods:
- Utilized gene knock-out technology to create mice deficient in the CaM-kinase alpha subunit.
- Employed a focal model of cerebral ischemia to induce stroke.
- Quantified infarct volume in homozygous knock-out, heterozygous, and wild-type mice.
Main Results:
- Homozygous knock-out mice (lacking CaM-kinase alpha subunit) exhibited nearly double the infarct volume compared to wild-type litter mates.
- Heterozygous mice also showed significantly larger infarct volumes than wild-type controls.
- These findings indicate a dose-dependent effect of CaM-kinase alpha subunit levels on ischemic damage.
Conclusions:
- Reduced levels of the CaM-kinase alpha subunit predispose neurons to increased damage following cerebral ischemia.
- Any factor decreasing CaM-kinase alpha subunit amount or activity enhances susceptibility to neuronal injury.
- CaM-kinase alpha subunit is a critical protective factor against ischemic brain damage.