The Presenilins as G-Protein Coupled Receptors

作为 G 蛋白偶联受体的早老素

• 批准号: 7316569
• 负责人: NAZNEEN N DEWJI
• 金额: $ 33.8万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7316569
• 关键词: Alzheimer' s Disease; Binding; Brain; Cell physiology; Cells; Commit; Communities; Condition; Coupling; Etiology; Event; Family; G-Protein-Coupled Receptors; GTP-Binding Proteins; Heterotrimeric GTP-Binding Proteins; Homeostasis; Integral Membrane Protein; Knowledge; Lead; Ligands; Mediating; Membrane; Molecular; Normal Cell; Outcome Study; Pharmacotherapy; Protein Binding; Proteins; Public Health; Publishing; Regulation; Research; Role; Signal Transduction; Structure; System; Work; design; inhibitor/antagonist; presenilin; presenilin-1; presenilin-2; protein activation; receptor function

DESCRIPTION (provided by applicant): THE PRESENILINS AS G-PROTEIN COUPLED RECEPTORS Our evidence (1,2) for a 7-TM structure for the Presenilins (PS) has led us to question whether PS-1 and PS- 2 belong to the GPCR superfamily of proteins, which all share essentially a similar structure. Previous work by others (3) has shown G-protein activation by PS-1, although these findings have been ignored, presumably because the 8-TM structure of the presenilins has been nearly universally accepted by the field over the last several years. Our hypothesis is that in such a system, the activation of PS would lead to G- protein binding, which in other systems, modulates many downstream signaling events. Regulation of the proposed GPCR function of PS-1 and PS-2 may therefore have consequences for Alzheimer's disease. Our specific aims are as follows: 1. To further confirm and extend the molecular details of G-protein binding to PS-1 and PS-2 (the latter not having been previously studied). 2. To investigate whether the GPCR function of PS-1 and PS-2 modulates the Ca2+ homeostasis that is frequently perturbed in the cell in Alzheimer's disease. 3. To investigate a possible role of membrane-bound B-APP as a specific ligand for PS-1 and PS-2 that regulates their GPCR activity, both in connection with normal cell physiology, and with the mechanisms involved in the etiology of Alzheimer's disease. Relevance to Public Health: Significance for Alzheimer's Disease: If our proposed studies elucidate Presenilin:G-protein coupling to indeed be significant to the mechanism by which PS mediates Ca2+ homeostasis in Alzheimer's disease, or/and they show that ¿-APP is the ligand that specifically activates PS-Go coupling, then a possible outcome of these studies might be a drug therapy for Alzheimer's disease using appropriately designed inhibitors of PS-Go specific binding.

描述（通过应用程序证明）：presenilins作为G蛋白耦合受体，我们的证据（1,2）是Presenilins（PS）的7-TM结构（PS）S导致我们质疑PS-1和PS-2是否属于PS-1和PS-2 GPCR的蛋白质基本上是类似的结构。因此，可能具有阿尔茨海默氏病的疾病。在阿尔茨海默氏病中的细胞中，要研究膜结合的应用程序作为PS-2的特异性配体的可能作用，以调节其GPCR活性，这均与正常的细胞生理学有关：对阿尔茨海默氏病的意义：如果我们的支撑研究阐明了presenilin：G蛋白偶联到Imer病的重要机制，或者它们表明„表明。 -App是指规范的配体，研究的可能结果可能是使用适当设计的PS-GO特异性结合的抑制剂。