The Presenilins as G-Protein Coupled Receptors

描述(申请人提供)：早老素作为G蛋白偶联受体我们的证据(1，2)证明早老素(PS)有一个7-TM结构，这让我们质疑PS-1和PS-2是否属于GPCR超家族蛋白质，它们基本上都有相似的结构。前人的工作(3)显示了PS-1对G蛋白的激活，尽管这些发现被忽略了，可能是因为在过去的几年里，早老素的8-TM结构几乎被该领域普遍接受。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，而在其他系统中，G蛋白结合调节许多下游信号事件。因此，PS-1和PS-2拟议的gpr功能的调节可能会对阿尔茨海默病产生影响。我们的具体目标如下：1.进一步确认和扩展G蛋白与PS-1和PS-2(后者以前没有被研究过)结合的分子细节。2.探讨PS-1和PS-2的GPCR功能是否调节阿尔茨海默病患者细胞内经常受到干扰的钙稳态。3.研究膜结合的B-APP作为PS-1和PS-2的特异性配体在调节PS-1和PS-2活性方面的可能作用，这既与正常细胞生理有关，也与阿尔茨海默病的发病机制有关。与公共健康相关：对阿尔茨海默病的意义：如果我们拟议的研究阐明了早老素：G蛋白偶联确实对PS介导阿尔茨海默病的钙稳态的机制具有重要意义，或者/并且它们表明β-APP是专门激活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特异性结合的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.