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Cerebral Cortex Advance Access originally published online on July 6, 2004
Cerebral Cortex 2005 15(1):74-84; doi:10.1093/cercor/bhh110
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Cerebral Cortex V 15 N 1 © Oxford University Press 2005; all rights reserved

Article

D1 Dopamine Receptor Regulation of the Levels of the Cell-cycle-controlling Proteins, Cyclin D, P27 and Raf-1, in Cerebral Cortical Precursor Cells is Mediated Through cAMP-independent Pathways

Ling Zhang1, Jie Bai1, Ashiwel S. Undie2, Clare Bergson3 and Michael S. Lidow1

1 Department of Biomedical Sciences, University of Maryland, Baltimore, MD 21201, USA, 2 Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD 21201, USA and 3 Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912, USA

Previously, we demonstrated that dopamine D1 receptor (D1R) agonists inhibit epidermal growth factor (EGF)-induced passage of mouse fetal cerebral cortical precursor cells from the G1 phase to the S phase of the cell cycle. Here, we report that this action of D1R agonists may involve regulation of cyclin D, and P27, which respectively promote and suppress the G1 to S transition. Furthermore, regulation of Raf-1, a component of the receptor tyrosine kinase mitogen-activated protein kinase pathway engaged in the mitogenic activity of EGF, may also be involved. Specifically, levels of cyclin D and Raf-1 decrease, whereas those of P27 first increase and then decrease in a dose-dependent fashion in response to the D1R agonist, SKF38393 This agonist also promotes Raf-1 phosphorylation on serine 338 residue, suggesting increased activation of this protein. Only the latter effect can be blocked by adenylyl cyclase (AC) and cAMP-dependent protein kinase A (PKA) inhibitors, and mimicked by agonists of the cAMP signaling pathway. Another D1R agonist, SKF83959 which stimulates phospholipase Cß (PLCß) but not AC, reduces levels of Raf-1 and cyclin D similar to SKF38393 However, we detected only down-regulation of P27 by this agonist. Additionally, the concentration-dependent patterns of both SKF38393 and SKF83959induced alterations in the levels of P27 closely resemble the effects of these ligands on the levels of the D1R–PLCß-associated second-messenger cascades linker, calcyon. These findings suggest that D1R-induced suppression of the cell cycle progression in EGF-supported fetal cortical precursor cells represents a net effect of competing cell cycle promoting and inhibiting molecular changes, which involve cyclin D, P27 and Raf-1. The data also show that cAMP second messenger cascade is not engaged in the D1R-induced regulation of the levels of these three proteins. Such regulation probably involves PLCß-associated pathways.


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