Drug Design: Glutamate Receptor Signaling

越来越多的证据表明，谷氨酸受体信号，通过AMPA/海人藻酸和NMDA 受体，在药物寻找反应中起着机械作用，成瘾是谷氨酸的一种形式- 依赖可塑性。事实上，最近的研究表明，反复服用可卡因会改变 戒断过程中海人藻酸受体的表达水平。AMPA/海人藻酸与NMDA受体 拮抗剂有可能出现与酒精和其他药物成瘾有关的临床症状。 尽管存在许多亚型的AMPA、海人藻酸和NMDA受体，但已证明很难 开发亚型特异性拮抗剂很大程度上是因为它们具有很高的同源性。相比之下，谷氨酸 受体亚型通过不同的分子支架偶联到不同的细胞内信号转导通路 蛋白质，包括突触相关蛋白(SAP)、谷氨酸受体相互作用蛋白 (夹点)，以及蛋白质与C激酶相互作用(Pick)。这些蛋白质含有PDZ(突触后密度- 95/Discs大/阻断区-1)结构域显示不同程度的受体亚型特异性。 SAP(例如，SAPg0和SAP97)由五个单独的域组成：三个PDZ域_DZ1， PDZ2、PDZ3)、Src同源3结构域(SH3)和鸟氨酸激酶型结构域(GK)。分子内 SAP的不同结构域之间的相互作用已被证明可以调节功能。在这里我们 建议开发多肽和多肽仿制药，以扰乱 这些分子支架蛋白。我们的目标是从结构上描述以下各项的域间相互作用 SAPg0、SAP97、GRIP和PICK使用高分辨率核磁共振和计算机模拟。合并 实验确定了这些支架的详细分子模型的结构特征 蛋白质将允许合理设计这些相互作用的分子抑制剂。这样的分子 将允许更好地理解特定的蛋白质-蛋白质相互作用以及提供一种 治疗药物成瘾的新途径。

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.