Protein-Protein Coupling/Uncoupling Enables Dopamine D<sub>2</sub>Receptor Regulation of AMPA Receptor-Mediated Excitotoxicity

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<jats:p>There is considerable evidence that dopamine D<jats:sub>2</jats:sub>receptors can modulate AMPA receptor-mediated neurotoxicity. However, the molecular mechanism underlying this process remains essentially unclear. Here we report that D<jats:sub>2</jats:sub>receptors inhibit AMPA-mediated neurotoxicity through two pathways: the activation of phosphoinositide-3 kinase (PI-3K) and downregulation of AMPA receptor plasma membrane expression, both involving a series of protein-protein coupling/uncoupling events. Agonist stimulation of D<jats:sub>2</jats:sub>receptors promotes the formation of the direct protein-protein interaction between the third intracellular loop of the D<jats:sub>2</jats:sub>receptor and the ATPase<jats:italic>N</jats:italic>-ethylmaleimide-sensitive factor (NSF) while uncoupling the NSF interaction with the carboxyl tail (CT) of the glutamate receptor GluR2 subunit of AMPA receptors. Previous studies have shown that full-length NSF directly couples to the GluR2<jats:sub>CT</jats:sub>and facilitates AMPA receptor plasma membrane expression. Furthermore, the CT region of GluR2 subunit is also responsible for several other intracellular protein couplings, including p85 subunit of PI-3K. Therefore, the direct coupling of D<jats:sub>2</jats:sub>-NSF and concomitant decrease in the NSF-GluR2 interaction results in a decrease of AMPA receptor membrane expression and an increase in the interaction between GluR2 and the p85 and subsequent activation of PI-3K. Disruption of the D<jats:sub>2</jats:sub>-NSF interaction abolished the ability of D<jats:sub>2</jats:sub>receptor to attenuate AMPA-mediated neurotoxicity by blocking the D<jats:sub>2</jats:sub>activation-induced changes in PI-3K activity and AMPA receptor plasma membrane expression. Furthermore, the D<jats:sub>2</jats:sub>-NSF-GluR2-p85 interactions are also responsible for the D<jats:sub>2</jats:sub>inhibition of ischemia-induced cell death. These data may provide a new avenue to identify specific targets for therapeutics to modulate glutamate receptor-governed diseases, such as stroke.</jats:p>

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