Effects of manganese on tyrosine hydroxylase (TH) activity and TH-phosphorylation in a dopaminergic neural cell line
Manganese (Mn) exposure causes manganism, a neurological disorder similar to Parkinson's disease. However, the cellular mechanism by which Mn impairs the dopaminergic neurotransmitter system remains unclear. We previously demonstrated that caspase-3-dependent proteolytic activation of protein kinase C delta (PKC{delta}) plays a key role in Mn-induced apoptotic cell death in dopaminergic neurons. Recently, we showed that PKC{delta} negatively regulates tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, by enhancing protein phosphatase-2A activity in dopaminergic neurons. Here, we report that Mn exposure can affect the enzymatic activity of TH, the rate-limiting enzyme in dopamine synthesis, by activating PKC{delta}-PP2A signaling pathway in a dopaminergic cell model. Low dose Mn (3-10 {mu}M) exposure to differentiated mesencephalic dopaminergic neuronal cells for 3 h induced a significant increase in TH activity and phosphorylation of TH-Ser40. The PKC{delta} specific inhibitor rottlerin did not prevent Mn-induced TH activity or TH-Ser40 phosphorylation. On the contrary, chronic exposure to 0.1-1 {mu}M Mn for 24 h induced a dose-dependent decrease in TH activity. Interestingly, chronic Mn treatment significantly increased PKC{delta} kinase activity and protein phosphatase 2A (PP2A) enzyme activity. Treatment with the PKC{delta} inhibitor rottlerin almost completely prevented chronic Mn-induced reduction in TH activity, as well as increased PP2A activity. Neither acute nor chronic Mn exposures induced any cytotoxic cell death or altered TH protein levels. Collectively, these results demonstrate that low dose Mn exposure impairs TH activity in dopaminergic cells through activation of PKC{delta} and PP2A activity.
- OSTI ID:
- 21587780
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 254, Issue 2; Conference: TRAC 2008/2009 meeting: 2008 Toxicology and Risk Assessment Conference;2009 Toxicology and Risk Assessment Conference, West Chester, OH (United States);West Chester, OH (United States), 14-17 Apr 2008;27-30 Apr 2009; Other Information: DOI: 10.1016/j.taap.2010.03.023; PII: S0041-008X(11)00049-4; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
APOPTOSIS
CHRONIC EXPOSURE
DOPAMINE
DOSES
ENZYME ACTIVITY
HYDROXYLASES
MANGANESE
NERVE CELLS
NERVOUS SYSTEM DISEASES
PHOSPHORYLATION
SYNTHESIS
TYROSINE
AMINES
AMINO ACIDS
ANIMAL CELLS
AROMATICS
AUTONOMIC NERVOUS SYSTEM AGENTS
CARBOXYLIC ACIDS
CARDIOTONICS
CARDIOVASCULAR AGENTS
CHEMICAL REACTIONS
DISEASES
DRUGS
ELEMENTS
ENZYMES
HYDROXY ACIDS
HYDROXY COMPOUNDS
METALS
NEUROREGULATORS
ORGANIC ACIDS
ORGANIC COMPOUNDS
OXIDOREDUCTASES
PHENOLS
POLYPHENOLS
PROTEINS
SOMATIC CELLS
SYMPATHOMIMETICS
TRANSITION ELEMENTS