Dopamine induces phenotypic differentiation or apoptosis in a dose-dependent fashion: involvement of the dopamine transporter and p53.
The effect of dopamine on the growth, phenotypes (morphological and biochemical) and programmed cell death (apoptosis) of the human neuronal NMB cell line was examined. Exposure to 20-50 microM of dopamine decreased cell growth, induced an apparent differentiated cell morphology and increased (3)H-dopamine uptake. At higher concentrations (100-300 microM) dopamine was neurotoxic and induced apoptosis, as reported previously. The observed effects of both low and high doses of dopamine were blocked by cocaine, which suggested involvement of dopamine transporters. Indeed, several experiments demonstrated the relationship between dopamine uptake of cells and their vulnerability to the toxic effect of dopamine. High concentrations of dopamine, which induced apoptosis, also increased p53 levels, detected by RT-PCR analysis and immunoblotting, whereas lower dopamine concentrations, which induced a differentiated phenotype, did not increase p53 immunoblotting. Dibutyryl-cAMP and dimethyl sulfoxide, which induced differentiation but not apoptosis of the NMB cells, did not increase p53 expression. These findings provide an insight into the role of dopamine, dopamine transporters and p53 in the differentiation and apoptosis of dopaminergic neurons, which will further our understanding of neuronal development and neurodegenerative diseases.
Porat
S
S
Department of Molecular Genetics, Weizman Institute of Science, Rehovot, Israel.
Premkumar
A
A
Simantov
R
R
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000196:embryology* / Q000378:metabolism / Q000503:physiopathology; D003994:Bucladesine / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D003042:Cocaine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism* / Q000493:pharmacokinetics; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D050483:Dopamine Plasma Membrane Transport Proteins; D016166:Free Radical Scavengers; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D016159:Tumor Suppressor Protein p53; D003994:Bucladesine; D003042:Cocaine; D004298:Dopamine