title: Nuclear Translocation of Calcium/Calmodulin-dependent Protein Kinase IIδ3 Promoted by Protein Phosphatase-1 Enhances Brain-derived Neurotrophic Factor Expression in Dopaminergic Neurons.
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 Ser(332) 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 Ser(332) by PP1 likely accounts for BDNF expression and subsequent neurite extension and survival of dopaminergic neurons.
authors.affiliation: From the Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan and shioda@m.tohoku.ac.jp.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Shioda
authors.affiliation: From the Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan and.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sawai
authors.affiliation: the Department of Neurobiology and Behavior, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Ishizuka
authors.affiliation: the Department of Neurobiology and Behavior, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Shirao
authors.affiliation: From the Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan and kfukunaga@m.tohoku.ac.jp.
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000068180:Aripiprazole / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000737:chemistry / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D010748:Phosphopeptides / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D010748:Phosphopeptides; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D012694:Serine; D000068180:Aripiprazole; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054645:Protein Phosphatase 1
keywords: BDNF; Ca2+/calmodulin-dependent protein kinase II (CaMKII); dopamine receptor; nuclear translocation; protein phosphatase 1 (PP1)