The Presenilins as G-Protein Coupled Receptors

描述（由申请人提供）：作为G蛋白偶联受体的早老素我们关于早老素（PS）的7-TM结构的证据（1，2）使我们怀疑PS-1和PS- 2是否属于蛋白质的GPCR超家族，这两种蛋白质基本上都具有相似的结构。其他人以前的工作（3）已经表明PS-1激活G蛋白，尽管这些发现被忽略了，可能是因为早老蛋白的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的激活将导致G蛋白结合，这在其他系统中，调节许多下游信号事件。因此，对PS-1和PS-2的GPCR功能的调节可能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结合的分子细节（后者以前没有研究过）。2.研究PS-1和PS-2的GPCR功能是否调节阿尔茨海默病细胞中经常受到干扰的Ca 2+稳态。3.研究膜结合的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，既与正常细胞生理学有关，又与阿尔茨海默病病因学相关的机制有关。与公共卫生的相关性：对阿尔茨海默病的意义：如果我们提出的研究阐明早老素：G-蛋白偶联确实对PS介导阿尔茨海默病中Ca 2+稳态的机制具有重要意义，或者/并且他们表明<$-APP是特异性激活PS-Go偶联的配体，那么这些研究的可能结果可能是使用适当设计的PS-Go特异性结合抑制剂对阿尔茨海默病进行药物治疗。

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.