The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway

Abstract

Toxic organic cations can damage nigrostriatal dopaminergic pathways as seen in most parkinsonian syndromes and in some cases of illicit drug exposure. Here, we show that the organic cation transporter 3 (Oct3) is expressed in nondopaminergic cells adjacent to both the soma and terminals of midbrain dopaminergic neurons. We hypothesized that Oct3 contributes to the dopaminergic damage by bidirectionally regulating the local bioavailability of toxic species. Consistent with this view, Oct3 deletion and pharmacological inhibition hampers the release of the toxic organic cation 1-methyl-4-phenylpyridinium from astrocytes and protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration in mice. Furthermore, Oct3 deletion impairs the removal of the excess extracellular dopamine induced by methamphetamine and enhances striatal dopaminergic terminal damage caused by this psychostimulant. These results may have far-reaching implications for our understanding of the mechanism of cell death in a wide range of neurodegenerative diseases and may open new avenues for neuroprotective intervention.astrocytes ͉ Parkinson's disease ͉ extraneuronal monoamine transporter ͉ dopamine ͉ methamphetamine

Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3

“…We recently reported that Oct3 can modulate toxicity in the dopaminergic system through its bidirectional transport capability of various toxic cations (12). In the present study, we asked whether this mechanism was also relevant to PQ 2+ .…”

“…This lack of DA reduction in wild-type mice despite a loss of DA neurons is proposed to be related to the compensatory up-regulation of TH activity in the striatum after PQ 2+ injection (9). On the basis of our previously proposed function of Oct3 in mediating the neurotoxicity of methamphetamine (12), it is possible that the striatal neurotoxicity observed in the Oct3 −/− mice was due to a reduced PQ buffering capacity in non-DA cells, and, hence, more PQ was available for DAT-mediated transport into DA terminals. To lend further support for this argument, we performed in vivo microdialysis to compare the functional effects of PQ 2+ treatment in freely moving Oct3 −/− and Oct3 +/+ mice.…”

“…Thus, although the microdialysis data suggest that, in the absence of Oct3 function, PQ somehow leads to striatal DA release and subsequent neurotoxicity, the mechanism for these effects is unclear, given that PQ 2+ does not appear to interact functionally with DAT on the basis of its inability to inhibit MPP + transport by DAT (Fig. 1E) (12). Despite its similar structure to MPP + , which is an excellent substrate for these transporters, we found that PQ 2+ was not taken up into cells through these transporters, as shown in the dose-response studies ( Fig.…”

“…Blocking DAT function abolished PQ + neurotoxicity in both cells and living mice. In addition to DAT, PQ + is also a substrate for the organic cation transporter-3 (Oct3), a bidirectional transporter that is highly expressed in astrocytes and GABAergic neurons in the nigrostriatal regions (12,13). Together, these two transporters function in a concerted manner to mediate nigrostriatal damage.…”

Cultured Astrocytes do not Release Adenosine during Hypoxic Conditions

“…The analyses were performed using CoulArray 5600A HPLC system (ESA Inc., Sunnyvale, CA, USA) and a model 526 UV detector (ESA Inc.) as previously described (Cui et al, 2009;Goldman et al, 2010). Chromatographic separation was achieved by using a Lichrospher 100 RP-18 column (5 mm, 250 mm  3 mm; Merck, KGaA, Darmstadt, Germany).…”