Drug Design: Glutamate Receptor Signaling

越来越多的证据表明，谷氨酸受体信号，通过AMPA/红藻氨酸和NMDA 受体，在药物寻求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，重复服用可卡因会改变 海人酸盐受体在戒断过程中的表达水平。AMPA/红藻氨酸和NMDA受体 拮抗剂具有与酒精和其它药物成瘾相关的临床综合征的潜力。 尽管存在AMPA、红藻氨酸盐和NMDA受体的许多亚型，但已证明很难将它们结合起来。 开发亚型特异性拮抗剂主要是因为它们的高度同源性。相反，谷氨酸 受体亚型通过不同的分子支架与不同的细胞内信号级联反应偶联 蛋白质，包括突触相关蛋白（SAP）、谷氨酸受体相互作用蛋白 （GRIPs）和蛋白质相互作用C激酶（PICK）。这些蛋白质含有PDZ（突触后密度- 95/盘状大/封闭带-1）结构域显示不同程度的受体亚型特异性。 SAP（例如，SAPg 0和SAP 97）由五个独立的结构域组成：三个PDZ结构域_DZ1， PDZ 2、PDZ 3）、src-同源3结构域（SH 3）和鸟苷激酶样结构域（GK）。分子内 SAP的不同结构域之间的相互作用已经显示出调节功能。这里我们 建议开发肽和肽模拟物，将破坏相互作用和内部的相互作用， 这些分子支架蛋白。我们的目标是在结构上表征结构域间的相互作用， sAPg 0、SAP 97、GRIP和PICK使用高分辨率NMR和计算机模拟。结合 将实验确定的结构特征转化为这些支架的详细分子模型 蛋白质将允许这些相互作用的分子抑制剂的合理设计。此类分子 将允许更好地理解特定的蛋白质-蛋白质相互作用，并提供 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.