Nitric oxide prevents phosphorylation of neuronal nitric oxide synthase at Serine1412 by inhibiting the Akt/PKB and CaM-K II signaling pathways

Tao Song, Naoya Hatano, Katsuyoshi Sugimoto, Mariko Horii, Fuminori Yamaguchi, Masaaki Tokuda, Yoshiaki Miyamoto, Toshie Kambe, Yasuo Watanabe

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Neuronal nitric oxide synthase (nNOS) is an important regulatory enzyme in the central nervous system catalyzing the production of NO, which regulates multiple biological processes in the central nervous system. However, the mechanisms by which nNOS activity is regulated are not completely understood. In the present study, the effects of protein kinases on the phosphorylation of nNOS in GH3 rat pituitary tumor cells were evaluated. We show that phosphorylation of nNOS at Ser1412 could be induced by the phosphatidylinositol 3-kinase/protein kinase B (Akt/PKB) agonist insulin, the calcium/calmodulin- dependent protein kinase II (CaM-K II) agonist A23187 or the cAMP-dependent protein kinase A (PKA) agonist IBMX, respectively. The phosphorylation levels of nNOS at Ser1412, induced by activation of Akt/PKB or CaM-K II, but not by PKA signaling, were reduced by pre-treatment with the NO donor diethylamine-NONOate. This inhibitory effect could be reversed by addition of a reducing reagent, dithiothreitol. Furthermore, the levels of phosphorylation of nNOS at Ser1412, induced by Akt/PKB or CaM-K II but not by PKA signaling, were enhanced by inhibition of nNOS activity with 7-nitroindazole. These findings suggest that the activation of nNOS can be catalyzed by at least three protein kinases, Akt/PKB, CaM-K II or PKA. NO generated from nNOS feedback prevents the activation of nNOS by inhibiting either Akt/PKB or CaM-K II but not PKA signaling.

Original languageEnglish
Pages (from-to)15-20
Number of pages6
JournalInternational journal of molecular medicine
Volume30
Issue number1
DOIs
Publication statusPublished - Jul 1 2012
Externally publishedYes

Keywords

  • Calcium/calmodulin-dependent protein kinase II
  • GH3 cells
  • Neuronal nitric oxide synthase
  • Phosphatidylinositol 3-kinase/protein kinase B
  • Phosphorylation
  • Protein kinase A

ASJC Scopus subject areas

  • Genetics

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