Key result
Down-regulation of B56δ expression using RNAi significantly increased dopamine synthesis from 1.59 to 3.69 μg/mg protein in N27 cells.
Absolute Event Rate: 3.69% vs 1.59%
p-value: p=<0.01
Tyrosine hydroxylase, which plays a critical role in regulation of dopamine synthesis, is known to be controlled by phosphorylation at several critical sites. One of these sites, Ser40, is phosphorylated by a number of protein kinases, including protein kinase A. The major protein phosphatase that dephosphorylates Ser40 is protein phosphatase-2A (PP2A). A recent study has also linked protein kinase C to the dephosphorylation of Ser40 [1], but the mechanism is unclear. PP2A isoforms are comprised of catalytic, scaffold, and regulatory subunits, the regulatory B subunits being able to influence cellular localization and substrate selection. In the current study, we find that protein kinase C is able to phosphorylate a key regulatory site in the B56δ subunit leading to activation of PP2A. In turn, activation of the B56δ-containing heterotrimeric form of PP2A is responsible for enhanced dephosphorylation of Ser40 of tyrosine hydroylase in response to stimulation of PKC. In support of this mechanism, down-regulation of B56δ expression in N27 cells using RNAi was found to increase dopamine synthesis. Together these studies reveal molecular details of how protein kinase C is linked to reduced tyrosine hydroxylase activity via control of PP2A, and also add to the complexity of protein kinase/protein phosphatase interactions.
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Ahn et al. (2011) studied this question. B56δ RNAi vs. Control RNAi was evaluated on Dopamine synthesis (μg/mg protein) (p=<0.01). Down-regulation of B56δ expression using RNAi significantly increased dopamine synthesis from 1.59 to 3.69 μg/mg protein in N27 cells.
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