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The Journal of Neuroscience, April 27, 2005, 25(17):4385-4395; doi:10.1523/JNEUROSCI.5099-04.2005

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Cellular/Molecular
Protein-Protein Coupling/Uncoupling Enables Dopamine D₂ Receptor Regulation of AMPA Receptor-Mediated Excitotoxicity

Shengwei Zou,¹ Lei Li,² Lin Pei,¹ Brian Vukusic,¹ Hubert H. M. Van Tol,^1,4,5 Frank J. S. Lee,¹ Qi Wan,^2,3 and Fang Liu^1,3,4,5

¹Department of Neuroscience, Centre for Addiction and Mental Health, ²Toronto Western Research Institute, Departments of ³Physiology and ⁴Psychiatry, and ⁵Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5T 1R8

There is considerable evidence that dopamine D₂ receptors can modulate AMPA receptor-mediated neurotoxicity. However, the molecular mechanism underlying this process remains essentially unclear. Here we report that D₂ 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 D₂ receptors promotes the formation of the direct protein-protein interaction between the third intracellular loop of the D₂ receptor and the ATPase N-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_CT 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 D₂-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 D₂-NSF interaction abolished the ability of D₂ receptor to attenuate AMPA-mediated neurotoxicity by blocking the D₂ activation-induced changes in PI-3K activity and AMPA receptor plasma membrane expression. Furthermore, the D₂-NSF-GluR2-p85 interactions are also responsible for the D₂ 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.

Key words: dopamine receptors; AMPA receptors; NSF; protein-protein interactions; cell death; PI-3 kinase; G-proteins

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Received Aug 24, 2004; revised March 19, 2005; accepted March 22, 2005.

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