Drug Design: Glutamate Receptor Signaling

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DESCRIPTION (provided by applicant): Recent studies provide strong evidence that glutamate receptor signaling, via both AMPA/kainate and NMDA receptors, play a mechanistic role in drug seeking responses and that addiction is a form of glutamate-dependent phisticity. AMPA/kainate and NMDA receptor antagonists have potential for clinical syndromes associated with addiction to alcohol and other drugs. Although numerous subtypes of AMPA, kainate, and NMDA receptors exist, it has proven difficult to develop subtype specific antagonists because of the high homology ot their ligand binding pockets. In contrast, glutamate receptor subtypes can couple to different intracellular signaling cascades via synaptic associated proteins (SAPs). SAPs (e.g., SAP9O and SAP97) are made up of five separate domains: three PDZ domains (PDZ1, PDZ2, PDZ3), a src-homology 3 domain (SH3), and a guanyl kinase-like domain (GK). Our studies show that the PDZ domains determine the selection of receptor subtype, while intra-molecular interactions between the different domains of SAPs regulate receptor function. Here we propose to develop peptides and peptidomimetics that will disrupt the molecular interactions of specific glutamate receptors with SAP90 and SAP97 and downstream signaling proteins. We aim to structurally characterize the inter-domain interactions of SAP90 and SAP97. To accomplish this, high-resolution NMR and computer simulations will be utilized to determine the structural features of PDZ1 and SH3 while complexed with the other domains of SAP90 and SAP97 as well as fragments from the NMDA, AMPA, and kainate receptors. The high-resolution structures will provide insight into the interactions between the receptors, SAPs, and regulatory proteins, which are responsible for the signaling, clustering and recycling of the receptors. Incorporating the experimentally determined structural features into detailed molecular models of SAP90 and SAP97 will allow for the rational design of molecular inhibitors of these interactions. Such molecules will allow for a greater understanding of the function of SAP90 and SAP97 as well as provide a novel route for the treatment of drug addiction.