Phosphorylation of neuronal nitric oxide synthase at Ser847 by CaM-KII in the hippocampus of rat brain after transient forebrain ischemia

Koji Osuka, Yasuo Watanabe, Nobuteru Usuda, Ayami Nakazawa, Kohji Fukunaga, Eishichi Miyamoto, Masakazu Takayasu, Masaaki Tokuda, Jun Yoshida

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29 Citations (Scopus)


The authors previously demonstrated that Ca2+/calmodulin (CaM)-dependent protein kinase IIα (CaMKIIα) can phosphorylate neuronal nitric oxide synthase (nNOS) at Ser847 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 Ser847 in the hippocampus. This nNOS phosphorylation appeared to be catalyzed by CaM-KII: (1) it correlated with the autophosphorylation of CaM-KIIα; (2) it was blocked by the CaM-KII inhibitor, KN-93; and (3) nNOS and CaM-KIIα were found to coexist in the hippocampus. Examination of the spatial relation between nNOS and CaM-KIIα in the brain revealed coexistence in the hippocampus but not in the cortex during reperfusion, with a concomitant increase in autophosphorylation of CaM-KIIα. The phosphorylation of nNOS at Ser847 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 Ser847 phosphorylation, and may thus contribute to promotion of tolerance to postischemic damage in hippocampal neurons.

Original languageEnglish
Pages (from-to)1098-1106
Number of pages9
JournalJournal of Cerebral Blood Flow and Metabolism
Issue number9
Publication statusPublished - 2002 Sept
Externally publishedYes


  • Calmodulin kinase IIα
  • Cerebral ischemia
  • Neuronal nitric oxide synthase
  • Phosphorylation

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine


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