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Journal article
A VITAL ROLE FOR Kv CHANNELS IN DOPAMINE TRANSPORTER-MEDIATED 6-HYDROXYDOPAMINE NEUROTOXICITY
Neuroscience, v 143(1)
04 Oct 2006
PMID: 17027171
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
6-hydroxydopamine (6-OHDA), a neurotoxic substrate of the dopamine transporter (DAT), is widely used in Parkinson’s disease models. However, the molecular mechanisms underlying 6-OHDA’s selectivity for dopamine neurons and the injurious sequelae that it triggers are not well understood. We tested whether ectopic expression of DAT induces sensitivity to 6-OHDA in non-dopaminergic cortical neurons and evaluated the contribution of Kv channel-dependent apoptosis to the toxicity of this compound in cortical and midbrain dopamine neurons. Cortical neurons expressing DAT accumulated dopamine and were highly vulnerable to 6-OHDA. Pharmacological inhibition of DAT completely blocked this toxicity. We also observed a p38-dependent Kv current surge in DAT-expressing cortical neurons exposed to 6-OHDA, and p38 antagonists and Kv channel blockers were neuroprotective in this model. Thus, DAT-mediated uptake of 6-OHDA recruited the oxidant-induced Kv channel dependent cell death pathway present in cortical neurons. Finally, we report that 6-OHDA also increased Kv currents in cultured midbrain dopamine neurons and this toxicity was blocked with Kv channel antagonists. We conclude that native DAT expression accounts for the dopamine neuron specific toxicity of 6-OHDA. Following uptake, 6-OHDA triggers the oxidant-associated Kv channel-dependent cell death pathway that is conserved in non-dopaminergic cortical neurons and midbrain dopamine neurons.
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Details
- Title
- A VITAL ROLE FOR Kv CHANNELS IN DOPAMINE TRANSPORTER-MEDIATED 6-HYDROXYDOPAMINE NEUROTOXICITY
- Creators
- Patrick T. Redman - University of PittsburghBahiyyah S. Jefferson - University of PittsburghChandra B. Ziegler - University of PittsburghOle V. Mortensen - University of PittsburghGonzalo E. Torres - University of PittsburghEdwin S. Levitan - University of PittsburghElias Aizenman - University of Pittsburgh
- Publication Details
- Neuroscience, v 143(1)
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000242109300001
- Scopus ID
- 2-s2.0-33750519461
- Other Identifier
- 991019319386604721
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- Web of Science research areas
- Neurosciences