Activation of phosphoinositide 3-kinase by D2 receptor prevents apoptosis in dopaminergic cell lines.
Whereas dopamine agonists are known to provide symptomatic benefits for Parkinson's disease, recent clinical trials suggest that they might also be neuroprotective. Laboratory studies demonstrate that dopamine agonists can provide neuroprotective effects in a number of model systems, but the role of receptor-mediated signalling in these effects is controversial. We find that dopamine agonists have robust, concentration-dependent anti-apoptotic activity in PC12 cells that stably express human D(2L) receptors from cell death due to H(2)O(2) or trophic withdrawal and that the protective effects are abolished in the presence of D(2)-receptor antagonists. D(2) agonists are also neuroprotective in the nigral dopamine cell line SN4741, which express endogenous D(2) receptors, whereas no anti-apoptotic activity is observed in native PC12 cells, which do not express detectable D(2) receptors. Notably, the agonists studied differ in their relative efficacy to mediate anti-apoptotic effects and in their capacity to stimulate [(35)S]guanosine 5'-[gamma-thio]triphosphate ([(35)S]GTP[S]) binding, an indicator of G-protein activation. Studies with inhibitors of phosphoinositide 3-kinase (PI 3-kinase), extracellular-signal-regulated kinase or p38 mitogen-activated protein kinase indicate that the PI 3-kinase pathway is required for D(2) receptor-mediated cell survival. These studies indicate that certain dopamine agonists can complex with D(2) receptors to preferentially transactivate neuroprotective signalling pathways and to mediate increased cell survival.
Nair
Venugopalan D
VD
Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
Olanow
C Warren
CW
Sealfon
Stuart C
SC
D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001971:Bromocriptine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects*; D004789:Enzyme Activation; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007700:Kinetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D016716:PC12 Cells; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D017448:Receptors, Dopamine D2; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D001971:Bromocriptine; D006861:Hydrogen Peroxide; D019870:1-Phosphatidylinositol 4-Kinase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases