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

ABSTRACT: The herbicide paraquat (PQ) has increasingly been reported in epidemiological studies to enhance the risk of developing Parkinson's disease (PD). Furthermore, case-control studies report that individuals with genetic variants in the dopamine transporter (DAT, SLC6A) have a higher PD risk when exposed to PQ. However, it remains a topic of debate whether PQ can enter dopamine (DA) neurons through DAT. We report here a mechanism by which PQ is transported by DAT: In its native divalent cation state, PQ(2+) is not a substrate for DAT; however, when converted to the monovalent cation PQ(+) by either a reducing agent or NADPH oxidase on microglia, it becomes a substrate for DAT and is accumulated in DA neurons, where it induces oxidative stress and cytotoxicity. Impaired DAT function in cultured cells and mutant mice significantly attenuated neurotoxicity induced by PQ(+). In addition to DAT, PQ(+) is also a substrate for the organic cation transporter 3 (Oct3, Slc22a3), which is abundantly expressed in non-DA cells in the nigrostriatal regions. In mice with Oct3 deficiency, enhanced striatal damage was detected after PQ treatment. This increased sensitivity likely results from reduced buffering capacity by non-DA cells, leading to more PQ(+) being available for uptake by DA neurons. This study provides a mechanism by which DAT and Oct3 modulate nigrostriatal damage induced by PQ(2+)/PQ(+) redox cycling.

SUBMITTER: Rappold PM

PROVIDER: S-EPMC3251116 | biostudies-other | 2011 Dec

REPOSITORIES: biostudies-other

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

Rappold Phillip M PM Cui Mei M Chesser Adrianne S AS Tibbett Jacqueline J Grima Jonathan C JC Duan Lihua L Sen Namita N Javitch Jonathan A JA Tieu Kim K

Proceedings of the National Academy of Sciences of the United States of America 20111205 51

The herbicide paraquat (PQ) has increasingly been reported in epidemiological studies to enhance the risk of developing Parkinson's disease (PD). Furthermore, case-control studies report that individuals with genetic variants in the dopamine transporter (DAT, SLC6A) have a higher PD risk when exposed to PQ. However, it remains a topic of debate whether PQ can enter dopamine (DA) neurons through DAT. We report here a mechanism by which PQ is transported by DAT: In its native divalent cation state ...[more]

PMID: 22143804

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Project description:The organic cation transporter (OCT) 3 is widely expressed in various organs in humans, and involved in the disposition of many exogenous and endogenous compounds. Several lines of evidence have suggested that OCT3 expressed in the brain plays an important role in the regulation of neurotransmission. Relative to wild-type (WT) animals, Oct3 knockout (KO) mice have displayed altered behavioral and neurochemical responses to psychostimulants such as amphetamine (AMPH) and methamphetamine. In the present study, both in vitro and in vivo approaches were utilized to explore potential mechanisms underlying the disparate neuropharmacological effects observed following AMPH exposure in Oct3 KO mice. In vitro uptake studies conducted in OCT3 transfected cells indicated that dextroamphetamine (d-AMPH) is not a substrate of OCT3. However, OCT3 was determined to be a high-capacity and low-affinity transporter for the neurotransmitters dopamine (DA), norepinephrine (NE), and serotonin (5-HT). Inhibition studies demonstrated that d-AMPH exerts relatively weak inhibitory effects on the OCT3-mediated uptake of DA, NE, 5-HT, and the model OCT3 substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide. The IC(50) values were determined to be 41.5 +/- 7.5 and 24.1 +/- 7.0 microM for inhibiting DA and 5-HT uptake, respectively, while 50% inhibition of NE and 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide uptake was not achieved by even the highest concentration of d-AMPH applied (100 microM). Furthermore, the disposition of d-AMPH in various tissues including the brain, liver, heart, kidney, muscle, intestine, spleen, testis, uterus, and plasma were determined in both male and female Oct3 KO and WT mice. No significant difference was observed between either genotypes or sex in all tested organs and tissues. Our findings suggest that OCT3 is not a prominent factor influencing the disposition of d-AMPH. Additionally, based upon the inhibitory potency observed in vitro, d-AMPH is unlikely to inhibit the uptake of monoamines mediated by OCT3 in the brain. Differentiated neuropharmacological effects of AMPHs noted between Oct3 KO and WT mice appear to be due to the absence of Oct3 mediated uptake of neurotransmitters in the KO mice.

Project description:IntroductionWe evaluated chr6q25.3 organic cation transporter gene (SLC22A1, SLC22A2, SLC22A3) variation and response to smoking cessation therapies. The corresponding proteins are low-affinity transporters of choline, acetylcholine and monoamines, and smoking cessation pharmacotherapies expressed in multiple tissues.MethodsWe selected 7 common polymorphisms for mega-regression analysis. We assessed additive model association of polymorphisms with 7-day point prevalence abstinence overall and by assigned pharmacotherapy at end of treatment and at 6 months among European-ancestry participants of 7 randomized controlled trials adjusted for demographic, population genetic, and trial covariates.ResultsInitial results were obtained in 6 trials with 1,839 participants. Nominally statistically significant associations of 2 SLC22A2 polymorphisms were observed: (1) with rs316019 at 6 months, overall ([c.808T>G; p.Ser270Ala], OR = 1.306, 95% CI = 1.034-1.649, p = .025), and among those randomized to nicotine replacement therapy (NRT) (OR = 1.784, 95% CI = 1.072-2.970, p = .026); and (2) with rs316006 (c.1502-529A>T) among those randomized to varenicline (OR = 1.420, 95% CI = 1.038-1.944, p = .028, OR = 1.362, 95% CI = 1.001-1.853, p = .04) at end of treatment and 6 months. Individuals randomized to NRT from a seventh trial were genotyped for rs316019; rs316019 was associated with a nominally statistically significant effect on abstinence overall at 6 months among 2,233 participants (OR = 1.249, 95% CI = 1.007-1.550, p = .043).ConclusionsThe functional OCT2 Ser270Ala polymorphism is nominally statistically significantly associated with abstinence among European-ancestry treatment-seeking smokers after adjustments for pharmacotherapy, demographics, population genetics, and without adjustment for multiple testing of 7 SNPs. Replication of these preliminary findings in additional randomized controlled trials of smoking cessation therapies and from multiple continental populations would describe another pharmacogenetic role for SLC22A2/OCT2.

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

Publications

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

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