ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2007
Protein kinase C delta negatively regulates tyrosine hydroxylase activity and dopamine synthesis by enhancing protein phosphatase-2A activity in dopaminergic neurons.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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59 citing papers in PubMed, 103 citations in OpenAlex.
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- Neuroprotective role for RORA in Parkinson's disease revealed by analysis of post-mortem brain and a dopaminergic cell line.NPJ Parkinson's disease · 2023Article
- CRISPR/Cas9 assisted stem cell therapy in Parkinson's disease.Biomaterials research · 2023Review
- Alzheimer's disease: Ablating single master site abolishes tau hyperphosphorylation.Science advances · 2022Article
- Garcinol blocks motor behavioural deficits by providing dopaminergic neuroprotection in MPTP mouse model of Parkinson's disease: involvement of anti-inflammatory response.Experimental brain research · 2022Article
- Clustered regularly interspaced short palindromic repeats as an advanced treatment for Parkinson's disease.Brain and behavior · 2021Review
- Fyn Kinase-Mediated PKCδ Y311 Phosphorylation Induces Dopaminergic Degeneration in Cell Culture and Animal Models: Implications for the Identification of a New Pharmacological Target for Parkinson's Disease.Frontiers in pharmacology · 2021Article
- NT5DC2 affects the phosphorylation of tyrosine hydroxylase regulating its catalytic activity.Journal of neural transmission (Vienna, Austria : 1996) · 2020Article
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- CRISPR System: A High-throughput Toolbox for Research and Treatment of Parkinson's Disease.Cellular and molecular neurobiology · 2020Review
- Mechanistic Interplay Between Autophagy and Apoptotic Signaling in Endosulfan-Induced Dopaminergic Neurotoxicity: Relevance to the Adverse Outcome Pathway in Pesticide Neurotoxicity.Toxicological sciences : an official journal of the Society of Toxicology · 2019Article
- Melatonin as a mitochondrial protector in neurodegenerative diseases.Cellular and molecular life sciences : CMLS · 2017Review
- p73 gene in dopaminergic neurons is highly susceptible to manganese neurotoxicity.Neurotoxicology · 2017Article
- The Anti-allergic Cromones: Past, Present, and Future.Frontiers in pharmacology · 2017Review
- Protein kinase Cδ upregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease.Neurobiology of disease · 2016Article
- Physiological TLR5 expression in the intestine is regulated by differential DNA binding of Sp1/Sp3 through simultaneous Sp1 dephosphorylation and Sp3 phosphorylation by two different PKC isoforms.Nucleic acids research · 2016Article
- Alterations in mitochondrial dynamics induced by tebufenpyrad and pyridaben in a dopaminergic neuronal cell culture model.Neurotoxicology · 2016Article
- Histone hyperacetylation up-regulates protein kinase Cδ in dopaminergic neurons to induce cell death: relevance to epigenetic mechanisms of neurodegeneration in Parkinson disease.The Journal of biological chemistry · 2014Article
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5 authors at 1 institution in 1 country.
Funding
Abstract
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 Cdelta (PKCdelta), and TH, in which the kinase modulates dopamine synthesis by negatively regulating TH activity via protein phosphatase 2A (PP2A). We observed that PKCdelta is highly expressed in nigral dopaminergic neurons and colocalizes with TH. Interestingly, suppression of PKCdelta activity with the kinase inhibitor rottlerin, PKCdelta-small interfering RNA, or with PKCdelta 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 PKCdelta not only physically associates with the PP2A catalytic subunit (PP2Ac) but also phosphorylates the phosphatase to increase its activity. Notably, inhibition of PKCdelta 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 PKCdelta knock-out (PKCdelta-/-) mouse model. Consistent with other results, we found greater TH-ser40 phosphorylation and reduced PP2A activity in the substantia nigra of PKCdelta-/- mice than in wild-type mice. Importantly, this was accompanied by an increased dopamine level in the striatum of PKCdelta-/- mice. Collectively, these results suggest that PKCdelta phosphorylates PP2Ac to enhance its activity and thereby reduces TH-ser40 phosphorylation and TH activity and ultimately dopamine synthesis.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.