Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 22, Issue 9, Pages 1098-1106Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/00004647-200209000-00007
Keywords
cerebral ischemia; calmodulin kinase II alpha; neuronal nitric oxide synthase; phosphorylation
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The authors previously demonstrated that Ca2+/calmodulin (CaM)-dependent protein kinase IIalpha (CaM-KIIalpha) can phosphorylate neuronal nitric oxide synthase (nNOS) at Ser(847) and attenuate NOS activity in neuronal cells. In the present study, they established that forebrain ischemia causes an increase in the phosphorylation of nNOS at Ser(847) in the hippocampus. This nNOS phosphorylation appeared to be catalyzed by CaM-KII: (1) it correlated with the autophosphorylation of CaM-KIIa; (2) it was blocked by the CaM-KII inhibitor, KN-93; and (3) nNOS and CaM-KIIalpha were found to coexist in the hippocampus. Examination of the spatial relation between nNOS and CaM-KIIalpha in the brain revealed co-existence in the hippocampus but not in the cortex during reperfusion, with a concomitant increase in autophosphorylation of CaM-KIIalpha. The phosphorylation of nNOS at Ser(847) probably takes place in nonpyramidal hippocampal neurons, which increased after 30 minutes of reperfusion in the hippocampus, whereas no significant increase was detected in the cortex. An intraventricular injection of KN-93 significantly decreased the phosphorylation of nNOS in the hippocampus. These results point to CaM-KII as a protein kinase, which by its colocalization may attenuate the activity of nNOS through its Ser(847) phosphorylation, and may thus contribute to promotion of tolerance to postischemic damage in hippocampal neurons.
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