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（适用提供）：作为G蛋白耦合受体的presenilins我们的证据（1,2）的7-TM结构（PS）导致我们质疑PS-1和PS-2是否属于蛋白质的GPCR超家族，这本质上都具有类似的结构。尽管这些发现被忽略了，但其他人（3）的先前工作（3）表明了G​​蛋白的激活，但大概是因为过去几年中，该领域的8-TM结构几乎已被该领域普遍接受。我们的假设是，在这样的系统中，PS的激活将导致G蛋白结合，在其他系统中，它调节了许多下游信号事件。因此，PS-1和PS-2的拟议GPCR功能的调节可能会对阿尔茨海默氏病产生影响。我们的具体目的如下：1。进一步确认并扩展G蛋白结合到PS-1和PS-2的分子细节（后者以前没有研究）。 2。研究PS-1和PS-2的GPCR功能是否调节了在阿尔茨海默氏病细胞中经常受到干扰的Ca2+稳态。 3。为了研究膜结合的b-app作为PS-1和PS-2的特定配体的可能作用，该配体调节其GPCR活性，包括与正常细胞生理学有关，以及与阿尔茨海默氏病的病因相关的机制。与公共卫生有关：阿尔茨海默氏病的意义：如果我们的拟议研究阐明了Presenilin：G蛋白耦合的确对PS介导的Alzheimer病中Ca2+稳态的机制确实很重要阿尔茨海默氏病使用适当设计的PS-GO特异性结合抑制剂。