A vital role for voltage-dependent potassium channels in dopamine transporter-mediated 6-hydroxydopamine neurotoxicity

Abstract

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

Apoptosis of Lactotrophs Induced by D2 Receptor Activation Is Estrogen Dependent

“…Dopaminergic neurons contain significant levels of DA, hydrogen peroxide and free iron that can lead to 6-OHDA formation through a nonenzymatic reaction between these elements [9]. Some studies suggest that 6-OHDA needs to be internalized by DAT to produce its cytotoxic effect [38, 39]. However, extracellular auto-oxidation of 6-OHDA was reported to induce oxidative stress and apoptosis [10].…”

Microglia induce neurotoxicity via intraneuronal Zn2+ release and a K+ current surge

“…We also observed that interfering with ASK-1 function, required for Kv2.1-mediated K 1 current surge (Aras and Aizenman, 2005), attenuated cell death. Finally, overexpression of a DN vector for Kv2.1, the K 1 channel responsible for mediating neuronal apoptosis in cortical, midbrain dopaminergic, and cerebellar granule neurons (Jiao et al, 2007;Pal et al, 2003;Redman et al, 2006), was also highly neuroprotective. Taken together, these results demonstrate that microglial-derived reactive species induce neuronal cell death via a process that involves the release of Zn 21 from intracellular sources, ASK-1 activation, and a surge in Kv2.1-mediated voltage-gated K 1 currents.…”

Apoptotic surge of potassium currents is mediated by p38 phosphorylation of Kv2.1

“…Blocking K ϩ channels, or increasing the extracellular K ϩ concentration, effectively attenuate cell death in many apoptotic models (2)(3)(4)(5)(6), including oxidant exposure in cortical and midbrain dopaminergic neurons (7)(8)(9)(10). With the use of dominant negative mutant subunits, Kv2.1, the major component of the delayed rectifier K ϩ current in neurons (11,12), was identified as the channel responsible for mediating the apoptotic K ϩ current surge in cortical neurons (13).…”