Nuclear Translocation of Calcium/Calmodulin-dependent Protein Kinase IIδ3 Promoted by Protein Phosphatase-1 Enhances Brain-derived Neurotrophic Factor Expression in Dopaminergic Neurons

Background: The physiological function of CaMKII3 phosphorylation at Ser(332) remains unclear. Results: CaMKII3 dephosphorylation at Ser(332) promotes its nuclear localization and stimulates BDNF expression. Conclusion: Dopamine D-2 receptor stimulation triggers CaMKII3 dephosphorylation at Ser(332) by PP1. Significance: CaMKII3 (Ser(332)) dephosphorylation is critical for neurite extension and survival of dopaminergic neurons. We have reported previously that dopamine D-2 receptor stimulation activates calcium/calmodulin-dependent protein kinase II (CaMKII) 3, a CaMKII nuclear isoform, increasing BDNF gene expression. However, the mechanisms underlying that activity remained unclear. Here we report that CaMKII3 is dephosphorylated at Ser(332) by protein phosphatase 1 (PP1), promoting CaMKII3 nuclear translocation. Neuro-2a cells transfected with CaMKII3 showed cytoplasmic and nuclear staining, but the staining was predominantly nuclear when CaMKII3 was coexpressed with PP1. Indeed, PP1 and CaMKII3 coexpression significantly increased nuclear CaMKII activity and enhanced BDNF expression. In support of this idea, chronic administration of the dopamine D-2 receptor partial agonist aripiprazole increased PP1 activity and promoted nuclear CaMKII3 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 PP1 knockdown. Taken together, nuclear translocation of CaMKII3 following dephosphorylation at Ser(332) by PP1 likely accounts for BDNF expression and subsequent neurite extension and survival of dopaminergic neurons.