Dopamine inhibits cell growth and cell cycle by blocking ribonucleotide reductase.
Dopamine (DA) is a classical neurotransmitter modulating various brain functions by acting on its specific receptors. In addition, DA is a reactive molecule that has been implicated in neurodegeneration, especially in Parkinson's disease. Here we show that DA inhibited cell growth of dopamine transporter transfected cells by intracellularly blocking cell cycle progression. To pinpoint the site of this effect, we measured DNA distribution and 5-bromo-2'-deoxyuridine (BrdU) incorporation, as well as the levels of the key cell cycle proteins. DA increased number of cells with a G1 DNA content, decreased BrdU incorporation and simultaneously increased cyclin A but had no effect on cyclin D2, D3, E, nor on cdk4 and p21. These results narrowed down the DA effect to the beginning of S phase, suggesting inhibition of the ribonucleotide reductase, an enzyme essential for DNA synthesis. Indeed, measurement of enzyme activity in situ revealed that DA, within 1h of addition to cells labelled with [3H]cytidine, strongly reduced the cell content of [3H]2'-deoxycytidine 5'-triphophate. The time course of this DA effect preceded the cell cycle progression. This novel molecular mechanism of intracellular DA action independent of plasmamembrane receptors may be involved in processes controlling the development and survival of brain dopaminergic neurons.
Woldman
Irina
I
Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria.
Reither
Harald
H
Kattinger
Alexandra
A
Hornykiewicz
Oleh
O
Pifl
Christian
C
D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D012264:Ribonucleotide Reductases; D004298:Dopamine