The Presenilins as G-Protein Coupled Receptors

我们对早老素（PS）的7-TM结构的证据（1,2）使我们质疑PS-1和PS- 2是否属于GPCR蛋白超家族，它们都具有基本相似的结构。其他人之前的工作(3)已经表明PS-1可以激活g蛋白，尽管这些发现被忽略了，可能是因为早老素的8-TM结构在过去几年中几乎被该领域普遍接受。我们的假设是，在这样一个系统中，PS的激活会导致G-蛋白结合，而在其他系统中，G-蛋白结合调节了许多下游信号事件。因此，调控PS-1和PS-2的GPCR功能可能对阿尔茨海默病有影响。我们的具体目标如下：进一步确认和扩展g蛋白与PS-1和PS-2结合的分子细节（后者此前未被研究）。2. 探讨PS-1和PS-2的GPCR功能是否调节阿尔茨海默病细胞中经常被扰乱的Ca2+稳态。3. 研究膜结合B-APP作为PS-1和PS-2的特异性配体调节其GPCR活性的可能作用，包括与正常细胞生理学和阿尔茨海默病病因学相关的机制。与公共卫生相关：对阿尔茨海默病的意义：如果我们提出的研究阐明了早老素：g蛋白偶联确实对阿尔茨海默病中PS介导Ca2+内平衡的机制有重要意义，或者/并且他们表明¿-APP是特异性激活PS- go偶联的配体，那么这些研究的一个可能的结果可能是使用适当设计的PS- go特异性结合抑制剂来治疗阿尔茨海默病。

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.