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Manganese induces sustained Ser40 phosphorylation and activation of tyrosine hydroxylase in PC12 cells
Author(s) -
Posser Thaís,
Franco Jeferson L.,
Bobrovskaya Larisa,
Leal Rodrigo B.,
Dickson Phillip W.,
Dunkley Peter R.
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06185.x
Subject(s) - phosphorylation , tyrosine hydroxylase , kinase , protein kinase a , protein phosphorylation , microbiology and biotechnology , chemistry , neurotoxicity , biochemistry , enzyme , biology , toxicity , organic chemistry
Manganese (Mn 2+ ) is an essential metal involved in normal functioning of a range of physiological processes. However, occupational overexposure to Mn 2+ causes neurotoxicity. The dopaminergic system is a particular target for Mn 2+ neurotoxicity. Tyrosine hydroxylase (TH) is the rate limiting enzyme for dopamine synthesis and is regulated acutely by phosphorylation at Ser40 and chronically by protein synthesis. In this study we used pheochromocytoma 12 cells to investigate the effects of Mn 2+ exposure on the phosphorylation and activity of TH. Mn 2+ treatment for 24 h caused a sustained increase in Ser40 phosphorylation and TH activity at a concentration of 100 μM, without altering the level of TH protein or PC12 cell viability. Inhibition of protein kinase A and protein kinase C and protein kinases known to be involved in sustained phosphorylation of TH in response to other stimuli did not block the effects of Mn 2+ on Ser40 phosphorylation. A substantial increase in H 2 O 2 production occurred in response to 100 μM Mn 2+ . The antioxidant Trolox TM completely inhibited H 2 O 2 production but did not block TH phosphorylation at Ser40, indicating that oxidative stress was not involved. Sustained TH phosphorylation at Ser40 and the consequent activation of TH both occurred at low concentrations of Mn 2+ and this provides a potential new mechanism for Mn 2+ ‐induced neuronal action that does not involve H 2 O 2 ‐mediated cell death.