Nuclear translocation of calcium/calmodulin-dependent protein kinase IIδ3 promoted by protein phosphatase-1 enhances brain-derived neurotrophic factor expression in dopaminergic neurons

Norifumi Shioda, Masahiro Sawai, Yuta Ishizuka, Tomoaki Shirao, Kohji Fukunaga

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

We have reported previously that dopamine D2 receptor stimulation activates calcium/calmodulin-dependent protein kinase II (CaMKII) δ3, a CaMKII nuclear isoform, increasing BDNF gene expression. However, the mechanisms underlying that activity remained unclear. Here we report that CaMKIIδ3 is dephosphorylated at Ser332 by protein phosphatase 1 (PP1), promoting CaMKIIδ3 nuclear translocation. Neuro-2a cells transfected with CaMKIIδ3 showed cytoplasmic and nuclear staining, but the staining was predominantly nuclear when CaMKIIδ3 was coexpressed with PP1. Indeed, PP1 and CaMKIIδ3 coexpression significantly increased nuclear CaMKII activity and enhanced BDNF expression. In support of this idea, chronic administration of the dopamine D2 receptor partial agonist aripiprazole increased PP1 activity and promoted nuclear CaMKIIδ3 translocation and BDNF expression in the rat brain substantia nigra. Moreover, aripiprazole treatment enhanced neurite extension and inhibited cell death in cultured dopaminergic neurons, effects blocked by PP1γ knockdown. Taken together, nuclear translocation of CaMKIIδ3 following dephosphorylation at Ser332 by PP1 likely accounts for BDNF expression and subsequent neurite extension and survival of dopaminergic neurons.

Original languageEnglish
Pages (from-to)21663-21675
Number of pages13
JournalJournal of Biological Chemistry
Volume290
Issue number35
DOIs
Publication statusPublished - 2015 Aug 28

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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