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.
Highlights
The physiological function of calmodulin-dependent protein kinase II (CaMKII)␦3 phosphorylation at Ser332 remains unclear
We show that the CaMKII␦3 Ser332 site is directly dephosphorylated by protein phosphatase 1 (PP1), promoting CaMKII␦3 nuclear translocation, and that aripiprazole (APZ), a dopamine D2 receptor (D2R) partial agonist, promotes CaMKII␦3 nuclear translocation and enhances BDNF expression
A pCaMKII (Thr286/Thr287) antibody recognized three bands with molecular masses corresponding to the ␣, , and ␦ subtypes (Fig. 1B, top panel, lane 5), and these bands disappeared upon treatment with PP1, a major Ser/Thr phosphatase expressed in eukaryotic cells (Fig. 1B, top panel, lane 6)
Summary
The physiological function of CaMKII␦3 phosphorylation at Ser332 remains unclear. Results: CaMKII␦3 dephosphorylation at Ser332 promotes its nuclear localization and stimulates BDNF expression. We have reported previously that dopamine D2 receptor stimulation activates calcium/calmodulin-dependent protein kinase II (CaMKII) ␦3, a CaMKII nuclear isoform, increasing BDNF gene expression. PP1 and CaMKII␦3 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 CaMKII␦3 translocation and BDNF expression in the rat brain substantia nigra. Nuclear translocation of CaMKII␦3 following dephosphorylation at Ser332 by PP1 likely accounts for BDNF expression and subsequent neurite extension and survival of dopaminergic neurons. We have demonstrated previously that CaMKII␦3 is highly expressed in dopaminergic rat substantia nigra (SN) neurons [24] and that stimulation of the dopamine D2 receptor (D2R) promotes CaMKII␦3 activation, thereby inducing BDNF gene expression in NG108-15 cells [25]. Our findings demonstrate a critical function for CaMKII␦3 nuclear translocation in promoting survival and enhancing neurite extension of dopaminergic neurons
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