Abstract6-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 DATexpressing 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 oxidantinduced 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 oxidantassociated Kv channel-dependent cell death pathway that is conserved in non-dopaminergic cortical neurons and midbrain dopamine neurons.Keywords potassium channels; dopamine transporter; 6-hydroxydopamine; neurotoxicity; p38; mitogen activated protein kinase Parkinson's disease is characterized by the loss of midbrain dopaminergic neurons. For over 35 years, the catecholamine-derived neurotoxin 6-hydroxydopamine (6-OHDA) has been used to induce dopaminergic cell death in various models of this disorder (Przedborski and Ischiropoulos, 2005). However, at sufficiently high concentrations all catecholamine derivatives, including dopamine and norepinephrine, induce non-selective cell death due to the