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

Autor: Shang, Tiesong, Uihlein, Alexander V., Van Asten, Jennifer, Kalyanaraman, Balaraman, Hillard, Cecilia J.
Předmět:
Zdroj: Journal of Neurochemistry; 4/15/2003, Vol. 85 Issue 2, p358-367, 10p
Abstrakt: Abstract 1-Methyl-4-phenylpyridinium (MPP[sup +]), 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[sup +] 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. [[sup 3]H]MPP[sup +] accumulation by CGNs exhibits first-order kinetics, and a K[sub t] value of 5.3 ± 1.2 µ m and a T[sub max] of 0.32 ± 0.02 pmol per min per 10[sup 6] cells . [[sup 3]H]MPP[sup +] accumulation is inhibited by corticosterone , β-estradiol and decynium 22 with K[sub i] values of 0.25 µ m, 0.17 µ m and 4.0 n m respectively . [[sup 3]H]MPP[sup +] accumulation is also inhibited by desipramine, dopamine, serotonin and norepinephrine, but is not affected by carnitine (10 m m), mazindol (9 µ m) or GBR 12909 (1 µ m). MPP[sup +]-induced caspase-3-like activation and cell death are prevented by pretreatment with 5 µ mβ-estradiol. In contrast, the neurotoxic effects of rotenone are unaffected by β-estradiol. Interestingly, GBR 12909 protects CGNs from both MPP[sup +] and rotenone toxicity. In summary, CGNs accumulate MPP[sup +] in manner that is consistent with uptake via OCT3 and the presence of this protein in CGNs explains their sensitivity to MPP[sup +] toxicity. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index