Drug Design: Glutamate Receptor Signaling

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Growing evidence indicates that glutamate receptor signaling, via both AMPA/kainate and NMDA receptors, plays a mechanistic role in drug seeking responses and that addiction is a form of glutamate- dependent plasticity. Indeed, it was recently shown that repeated administration of cocaine alters the expression levels of kainate receptors during withdrawal. 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 largely because of their high homology. In contrast, glutamate receptor subtypes couple to different intracellular signaling cascades via different molecular scaffolding proteins, including the synaptic associated proteins (SAPs), glutamate receptor-interacting proteins (GRIPs), and proteins interacts C kinases (PICK). These proteins contain PDZ (postsynaptic density- 95/Discs large/Zona occludens-1) domains displaying various extents of receptor subtype specificity. The SAPs (e.g., SAPg0 and SAP97) are made up of five separate domains: three PDZ domains _DZ1, PDZ2, PDZ3), a src-homology 3 domain (SH3), and a guanyl kinase-like domain (GK). Intra-molecular interactions between the different domains of the SAPs have been shown to regulate function. Here we propose to develop peptides and peptidomimetics that will disrupt the inter- and intra-interactions of these molecular scaffolding proteins. We aim to structurally characterize the inter-domain interactions of sAPg0, SAP97, GRIP, and PICK using high-resolution NMR and computer simulations. Incorporating the experimentally determined structural features into detailed molecular models of these scaffolding proteins will allow for the rational design of molecular inhibitors of these interactions. Such molecules will allow for a greater understanding of the specific protein-protein interactions as well as provide a novel route for the treatment of drug addiction.