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The Journal of Neuroscience, May 16, 2007, 27(20):5349-5362; doi:10.1523/JNEUROSCI.4107-06.2007

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Cellular/Molecular
Protein Kinase C Negatively Regulates Tyrosine Hydroxylase Activity and Dopamine Synthesis by Enhancing Protein Phosphatase-2A Activity in Dopaminergic Neurons

Danhui Zhang, Arthi Kanthasamy, Yongjie Yang, Vellareddy Anantharam, and Anumantha Kanthasamy

Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011

Correspondence should be addressed to Dr. A. G. Kanthasamy, Parkinson Disorders Research Laboratory, Department of Biomedical Sciences, Iowa State University, 2062 College of Veterinary Medicine Building, Ames, IA 50011. Email: akanthas{at}iastate.edu

Tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, can be regulated by phosphorylation at multiple serine residues, including serine-40. In the present study, we report a novel interaction between a key member of the novel PKC family, protein kinase C (PKC), and TH, in which the kinase modulates dopamine synthesis by negatively regulating TH activity via protein phosphatase 2A (PP2A). We observed that PKC is highly expressed in nigral dopaminergic neurons and colocalizes with TH. Interestingly, suppression of PKC activity with the kinase inhibitor rottlerin, PKC-small interfering RNA, or with PKC dominant-negative mutant effectively increased a number of key biochemical events in the dopamine pathway, including TH-ser40 phosphorylation, TH enzymatic activity, and dopamine synthesis in neuronal cell culture models. Additionally, we found that PKC not only physically associates with the PP2A catalytic subunit (PP2Ac) but also phosphorylates the phosphatase to increase its activity. Notably, inhibition of PKC reduced the dephosphorylation activity of PP2A and thereby increased TH-ser40 phosphorylation, TH activity, and dopamine synthesis. To further validate our findings, we used the PKC knock-out (PKC –/–) mouse model. Consistent with other results, we found greater TH-ser40 phosphorylation and reduced PP2A activity in the substantia nigra of PKC –/– mice than in wild-type mice. Importantly, this was accompanied by an increased dopamine level in the striatum of PKC–/– mice. Collectively, these results suggest that PKC phosphorylates PP2Ac to enhance its activity and thereby reduces TH-ser40 phosphorylation and TH activity and ultimately dopamine synthesis.

Key words: PKC; TH phosphorylation; dopamine synthesis; Parkinson's disease; PP2A; RNAi

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Received Sept. 19, 2006; revised April 6, 2007; accepted April 9, 2007.

Correspondence should be addressed to Dr. A. G. Kanthasamy, Parkinson Disorders Research Laboratory, Department of Biomedical Sciences, Iowa State University, 2062 College of Veterinary Medicine Building, Ames, IA 50011. Email: akanthas{at}iastate.edu

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