Faculty Collaboration Database

1-Methyl-4-phenylpyridinium accumulates in cerebellar granule neurons via organic cation transporter 3. J Neurochem 2003 Apr;85(2):358-67

Date

04/05/2003

Pubmed ID

12675912

DOI

10.1046/j.1471-4159.2003.01686.x

Scopus ID

2-s2.0-0344406174 (requires institutional sign-in at Scopus site)   72 Citations

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 micro m and a Tmax of 0.32 +/- 0.02 pmol per min per 106 cells. [3H]MPP+ accumulation is inhibited by corticosterone, beta-estradiol and decynium 22 with Ki values of 0.25 micro m, 0.17 micro m 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 micro m) or GBR 12909 (1 micro m). MPP+-induced caspase-3-like activation and cell death are prevented by pretreatment with 5 micro mbeta-estradiol. In contrast, the neurotoxic effects of rotenone are unaffected by beta-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.

Author List

Shang T, Uihlein AV, Van Asten J, Kalyanaraman B, Hillard CJ

Authors

Cecilia J. Hillard PhD Associate Dean, Center Director, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

1-Methyl-4-phenylpyridinium
Adrenergic Uptake Inhibitors
Animals
Anti-Inflammatory Agents
Biological Transport
Cell Survival
Cells, Cultured
Cerebellum
Corticosterone
Desipramine
Dopamine Uptake Inhibitors
Dose-Response Relationship, Drug
Drug Antagonism
Estradiol
Female
Male
Neurons
Neuroprotective Agents
Organic Cation Transport Proteins
Piperazines
Quinolines
RNA, Messenger
Rats
Rotenone
Temperature