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 D2L receptors from cell death due to H2O2 or trophic withdrawal and that the protective effects are abolished in the presence of D2-receptor antagonists. D2 agonists are also neuroprotective in the nigral dopamine cell line SN4741, which express endogenous D2 receptors, whereas no anti-apoptotic activity is observed in native PC12 cells, which do not express detectable D2 receptors. Notably, the agonists studied differ in their relative efficacy to mediate anti-apoptotic effects and in their capacity to stimulate [35S]guanosine 5′-[γ-thio]triphosphate ([35S]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 D2 receptor-mediated cell survival. These studies indicate that certain dopamine agonists can complex with D2 receptors to preferentially transactivate neuroprotective signalling pathways and to mediate increased cell survival.
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Research Article|
July 01 2003
Activation of phosphoinositide 3-kinase by D2 receptor prevents apoptosis in dopaminergic cell lines
Venugopalan D. NAIR;
Venugopalan D. NAIR
Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, U.S.A.
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C. Warren OLANOW;
C. Warren OLANOW
Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, U.S.A.
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Stuart C. SEALFON
Stuart C. SEALFON
1
Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, U.S.A.
1To whom correspondence should be addressed (e-mail stuart.sealfon@mssm.edu).
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Publisher: Portland Press Ltd
Received:
January 02 2003
Revision Received:
March 25 2003
Accepted:
April 08 2003
Accepted Manuscript online:
April 08 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 373 (1): 25–32.
Article history
Received:
January 02 2003
Revision Received:
March 25 2003
Accepted:
April 08 2003
Accepted Manuscript online:
April 08 2003
Citation
Venugopalan D. NAIR, C. Warren OLANOW, Stuart C. SEALFON; Activation of phosphoinositide 3-kinase by D2 receptor prevents apoptosis in dopaminergic cell lines. Biochem J 1 July 2003; 373 (1): 25–32. doi: https://doi.org/10.1042/bj20030017
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