Cytosolic Sulfotransferase 1A3 Is Induced by Dopamine and Protects Neuronal Cells from Dopamine Toxicity ROLE OF D1 RECEPTOR-N-METHYL-D-ASPARTATE RECEPTOR COUPLING

Background: Dopaminergic neurons are susceptible to dopamine-induced toxicity. Results: Dopamine induces the cytosolic sulfotransferase SULT1A3 via a dopamine D1-NMDA receptor-coupled mechanism. Conclusion: Induction of SULT1A3 significantly protects cells from dopamine neurotoxicity. Significance: The dysregulation of SULT1A3 expression may be a risk factor for neurodegenerative diseases involving dopamine. Dopamine neurotoxicity is associated with several neurodegenerative diseases, and neurons utilize several mechanisms, including uptake and metabolism, to protect them from injury. Metabolism of dopamine involves three enzymes: monoamine oxidase, catechol O-methyltransferase, and sulfotransferase. In primates but not lower order animals, a sulfotransferase (SULT1A3) is present that can rapidly metabolize dopamine to dopamine sulfate. Here, we show that SULT1A3 and a closely related protein SULT1A1 are highly inducible by dopamine. This involves activation of the D1 and NMDA receptors. Both ERK1/2 phosphorylation and calcineurin activation are required for induction. Pharmacological agents that inhibited induction or siRNA targeting SULT1A3 significantly increased the susceptibility of cells to dopamine toxicity. Taken together, these results show that dopamine can induce its own metabolism and protect neuron-like cells from damage, suggesting that SULT1A3 activity may be a risk factor for dopamine-dependent neurodegenerative diseases.