1-Methyl-4-phenylpyridinium accumulates in cerebellar granule neurons via organic cation transporter 3

Tiesong Shang, Alexander V. Uihlein, Jennifer Van Asten, Balaraman Kalyanaraman, Cecilia J. Hillard

Research output: Contribution to journalArticle

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Abstract

1-Methyl-4-phenylpyridinium (MPP+), the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, induces apoptosis in cerebellar granule neurons (CGNs). We have tested the hypothesis that organic cation transporter (OCT) 3 mediates the accumulation and, hence, the toxicity of MPP+ in CGNs. CGNs in primary culture express OCT3 but do not express mRNA for OCT1, OCT2 or the dopamine transporter. Cerebellar astrocytes are negative for OCT3 protein by immunocytochemistry. [3H]MPP+ accumulation by CGNs exhibits first-order kinetics, and a Kt value of 5.3 ± 1.2 μM and a Tmax of 0.32 ± 0.02 pmol per min per 106 cells. [3H]MPP+ accumulation is inhibited by corticosterone, β-estradiol and decynium 22 with Ki values of 0.25 μM, 0.17 μM and 4.0 nM respectively. [3H]MPP+ accumulation is also inhibited by desipramine, dopamine, serotonin and norepinephrine, but is not affected by carnitine (10 mM), mazindol (9 μM) or GBR 12909 (1 μM). MPP+-induced caspase-3-like activation and cell death are prevented by pretreatment with 5 μM β-estradiol. In contrast, the neurotoxic effects of rotenone are unaffected by β-estradiol. Interestingly, GBR 12909 protects CGNs from both MPP+ and rotenone toxicity. In summary, CGNs accumulate MPP+ in manner that is consistent with uptake via OCT3 and the presence of this protein in CGNs explains their sensitivity to MPP+ toxicity.

Original languageEnglish (US)
Pages (from-to)358-367
Number of pages10
JournalJournal of Neurochemistry
Volume85
Issue number2
StatePublished - Apr 2003

Fingerprint

1-Methyl-4-phenylpyridinium
Neurons
Cations
Toxicity
Rotenone
Estradiol
Mazindol
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Dopamine Plasma Membrane Transport Proteins
Desipramine
Carnitine
Poisons
Cell death
Corticosterone
Metabolites
Caspase 3
Astrocytes
Dopamine
Serotonin
Norepinephrine

Keywords

  • 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
  • Beta-estradiol
  • Caspase
  • Desipramine
  • GBR 12909
  • Rotenone

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Shang, T., Uihlein, A. V., Van Asten, J., Kalyanaraman, B., & Hillard, C. J. (2003). 1-Methyl-4-phenylpyridinium accumulates in cerebellar granule neurons via organic cation transporter 3. Journal of Neurochemistry, 85(2), 358-367.

1-Methyl-4-phenylpyridinium accumulates in cerebellar granule neurons via organic cation transporter 3. / Shang, Tiesong; Uihlein, Alexander V.; Van Asten, Jennifer; Kalyanaraman, Balaraman; Hillard, Cecilia J.

In: Journal of Neurochemistry, Vol. 85, No. 2, 04.2003, p. 358-367.

Research output: Contribution to journalArticle

Shang, T, Uihlein, AV, Van Asten, J, Kalyanaraman, B & Hillard, CJ 2003, '1-Methyl-4-phenylpyridinium accumulates in cerebellar granule neurons via organic cation transporter 3', Journal of Neurochemistry, vol. 85, no. 2, pp. 358-367.
Shang, Tiesong ; Uihlein, Alexander V. ; Van Asten, Jennifer ; Kalyanaraman, Balaraman ; Hillard, Cecilia J. / 1-Methyl-4-phenylpyridinium accumulates in cerebellar granule neurons via organic cation transporter 3. In: Journal of Neurochemistry. 2003 ; Vol. 85, No. 2. pp. 358-367.
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N2 - 1-Methyl-4-phenylpyridinium (MPP+), the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, induces apoptosis in cerebellar granule neurons (CGNs). We have tested the hypothesis that organic cation transporter (OCT) 3 mediates the accumulation and, hence, the toxicity of MPP+ in CGNs. CGNs in primary culture express OCT3 but do not express mRNA for OCT1, OCT2 or the dopamine transporter. Cerebellar astrocytes are negative for OCT3 protein by immunocytochemistry. [3H]MPP+ accumulation by CGNs exhibits first-order kinetics, and a Kt value of 5.3 ± 1.2 μM and a Tmax of 0.32 ± 0.02 pmol per min per 106 cells. [3H]MPP+ accumulation is inhibited by corticosterone, β-estradiol and decynium 22 with Ki values of 0.25 μM, 0.17 μM and 4.0 nM respectively. [3H]MPP+ accumulation is also inhibited by desipramine, dopamine, serotonin and norepinephrine, but is not affected by carnitine (10 mM), mazindol (9 μM) or GBR 12909 (1 μM). MPP+-induced caspase-3-like activation and cell death are prevented by pretreatment with 5 μM β-estradiol. In contrast, the neurotoxic effects of rotenone are unaffected by β-estradiol. Interestingly, GBR 12909 protects CGNs from both MPP+ and rotenone toxicity. In summary, CGNs accumulate MPP+ in manner that is consistent with uptake via OCT3 and the presence of this protein in CGNs explains their sensitivity to MPP+ toxicity.

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