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MBC in Press, published online ahead of print April 23, 2008
Mol. Biol. Cell 10.1091/mbc.E07-09-0980

A more recent version of this article appeared on July 1, 2008
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Submitted on September 28, 2007
Revised on April 3, 2008
Accepted on April 16, 2008

Genetic Complementation Screen Identifies a Map Kinase Phosphatase, MKP3, as a Regulator of Dopamine Transporter Trafficking

Ole Valente Mortensen,* Mads Breum Larsen,* Balakrishna Malasani Prasad,{dagger} and Susan Gaye Amara*

*Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260; {dagger}Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912

Monitoring Editor: Jean Gruenberg

The antidepressant and cocaine sensitive plasma membrane monoamine transporters are the primary mechanism for clearance of their respective neurotransmitters and serve a pivotal role in limiting monoamine neurotransmission. To identify molecules in pathways that regulate dopamine transporter (DAT) internalization we used a genetic complementation screen in Xenopus oocytes to identify a MAP kinase phosphatase, MKP3/Pyst1/DUSP6, as a molecule that inhibits Protein kinase C-induced (PKC) internalization of transporters, resulting in enhanced DAT activity. The involvement of MKP3 in DAT internalization was verified using both overexpression and shRNA knockdown strategies in mammalian cell models including a dopaminergic cell line. Although the isolation of MKP3 implies a role for MAP kinases in DAT internalization, MAP kinase inhibitors have no effect on internalization. Moreover, PKC-dependent down-regulation of DAT does not correlate with the phosphorylation state of several well-studied MAP kinases (ERK1/2, p38 and SAPK/JNK). We also show that MKP3 does not regulate PKC-induced ubiquitylation of DAT but acts at a more downstream step to stabilize DAT at the cell surface by blocking dynamin-dependent internalization and delaying the targeting of DAT for degradation. These results indicate that MKP3 can act to enhance DAT function and identifies MKP3 as a phosphatase involved in regulating dynamin dependent endocytosis.

Address correspondence to: Ole Valente Mortensen (mortense{at}pitt.Edu)






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