Journal article
Genetic Complementation Screen Identifies a Mitogen-activated Protein Kinase Phosphatase, MKP3, as a Regulator of Dopamine Transporter Trafficking
Molecular biology of the cell, v 19(7), pp 2818-2829
Jul 2008
PMID: 18434601
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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 mitogen-activated protein (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.
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Details
- Title
- Genetic Complementation Screen Identifies a Mitogen-activated Protein Kinase Phosphatase, MKP3, as a Regulator of Dopamine Transporter Trafficking
- Creators
- Ole Valente Mortensen - Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260; andMads Breum Larsen - Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260; andBalakrishna M Prasad - Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912Susan G Amara - Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260; and
- Contributors
- Jean Gruenberg (Editor)
- Publication Details
- Molecular biology of the cell, v 19(7), pp 2818-2829
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000259158200012
- Scopus ID
- 2-s2.0-51349157554
- Other Identifier
- 991014878399604721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Cell Biology