Molecular Mechanisms of Dopamine Receptor Mediated Neuroprotection
Abstract
Selective dopamine agonists acting at the D2 receptor (D2R) inhibit the toxicity caused by oxidative stress through a novel growth factor dependent and G protein independent signaling pathway. In response to oxidative stress, PC12 cells activate signaling pathways of both homeostasis, as represented by activation of extracellular regulated kinase (ERK) and pro-apoptotic responses as indicated by p53 activation. Individual cells segregate into two populations within the first hour of stress, either showing the activation of ERK or pre-apoptotic p53 activation. The D2 agonist, bromocriptine caused protein kinase B (Akt) activation in PC12-D2R cells and the inhibition of either phosphoinositide 3-kinase (PI3-K), epidermal growth factor receptor (EGFR) or c-Src eliminated the Akt activation and the cytoprotective effects of bromocriptine against oxidative stress. Co-immunoprecipitation and EGFR repression by inhibitor or by RNA interference, studies showed a cross-talk between these receptors in mediating the activation of Akt. D2R stimulation by bromocriptine induced c-Src and EGFR tyrosine phosphoryation. Furthermore, Src tyrosine kinase inhibitor or dominant negative Src interfered with Akt translocation and phosphorylation. We conclude that the predominant signaling cascade mediating cytoprotection by the D2 receptor involves c-Src/EGFR transactivation by D2R, activating PI3-K and Akt.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2003
- Accession Number
- ADA420123
Entities
People
- Stuart C. Sealfon
Organizations
- Icahn School of Medicine at Mount Sinai