G-protein-, beta-arrestin- and ERK-signaling in alcohol use- and anxiety-disorders

项目概要/摘要 G蛋白偶联受体（GPCR）长期以来一直是制药公司最喜欢的靶点， 治疗无数的疾病，因为它们很容易获得和无处不在的表达。的主要 GPCR的信号转导途径是通过同名的G蛋白途径和通过相互作用 用β-抑制蛋白连接的支架。包括我自己在内的几个研究小组已经确定，G- 蛋白质和β-抑制蛋白可以各自独特地调节行为类型。发现药物作用于 在GPCR中，可以表现出所谓的功能选择性[即仅激活一种途径而不激活另一种途径] 为开发具有较少副作用的信号偏向药物提供了新的机会。 虽然G蛋白和β-抑制蛋白主要提供信号级联的分歧，但也有一小部分信号级联是由G蛋白和β-抑制蛋白引起的。 酶在这两种途径中的作用不明确。特别令人感兴趣的是丝裂原活化蛋白 激酶“ERK”（细胞外信号调节激酶）。ERK的功能和功能障碍与 许多疾病和紊乱，如癌症、抑郁症和药物成瘾。大量研究 研究了G蛋白和β-arrestins如何调节ERK活性， 模型然而，由于缺乏特定的工具，很难确定G蛋白如何作用于细胞。 抑制蛋白介导的和β-抑制蛋白介导的ERK激活分别有助于行为的调节。 特别地，感兴趣的是ERK激活的总量是否是细胞凋亡背后的驱动力。 生理效应，或激活机制（G蛋白与β-抑制蛋白）是否重要。 最近的药理学进展使我们能够提出实验， 行为测定中G蛋白和β-抑制蛋白ERK激活的解剖。对于这个建议，我们将使用 G蛋白和β-抑制蛋白偏向药物作用于δ阿片受体，并利用创新的 化学遗传学方法来解决我们的研究问题。我们之前研究δ阿片类药物的研究 受体的研究表明，在该受体上使用G蛋白偏向性药物可以减少酒精使用，而 那些激活ERK的δ阿片类药物可以减轻焦虑。完成这项研究后，我们将能够 解决与酒精使用相关的信号传导偏置ERK激活的基本问题， 类似焦虑的行为更重要的是，我们将能够描述δ阿片受体的“偏见程度” 药物必须和如何/多少ERK应该能够激活，以有效地减少 酒精和焦虑同时存在这种药物将是非常有价值的，因为酒精的使用 焦虑症与一般性焦虑症和创伤后应激障碍高度共病。 此外，酒精戒断引起的焦虑是复发的主要原因，因此是一种双功能性的焦虑。 δ阿片类药物将是一个显着更好的治疗选择，患者患有酒精使用 比目前可用的治疗方案的障碍。

Project summary/Abstract G-protein coupled receptors (GPCRs) have long been a favorite target of pharmaceutical companies for treatment of myriad diseases as they are easily accessible and ubiquitously expressed. The predominant signal transduction routes for GPCRs are through the namesake G-protein pathway and by interaction with β-arrestin-linked scaffolds. Several research groups, including my own, have identified that G- proteins and β-arrestins can each uniquely modulate types of behavior. The discovery that drugs acting at GPCRs can exhibit so-called functional selectivity [i.e. activate only one pathway and not the other] has provided new opportunities for development of signaling biased drugs with fewer adverse effects. While G-proteins and β-arrestins mostly provide a divergence of signaling cascades, a small set of enzymes ambiguously play roles in both pathways. Of particular interest is the mitogen activated protein kinase `ERK' (extracellular signal-regulated kinase). ERK function and dysfunction has been linked to many diseases and disorders such as cancer, depression and drug addiction. Numerous studies have been conducted investigating how G-proteins and β-arrestins regulate ERK activity in simple cellular models. However, due to a lack of specific tools it has been much harder to establish how G-protein- mediated and β-arrestin-mediated ERK activation individually contribute to the modulation of behavior. Particularly it is of interest whether the total amount of ERK activation is the driving force behind the physiological effect, or whether the mechanism of activation (G-protein versus β-arrestin) is important. Recent pharmacological advances are now allowing us to propose experiments that will enable the dissection of G-protein and β-arrestin ERK activation in behavioral assays. For this proposal we will use G-protein and β-arrestin-biased drugs acting on delta opioid receptors as well as utilize innovative chemogenetic approaches to address our research questions. Our prior studies investigating delta opioid receptors have revealed that G-protein-biased drugs at this receptor can reduce alcohol use, whereas those delta opioids that activate ERK reduce anxiety. Upon completion of this study we will be able to address fundamental questions regarding signaling biased ERK activation related to alcohol use and anxiety-like behavior. More importantly, we will be able to describe `how biased' a delta opioid receptor drug must be and how /how much ERK it should be able to activate in order to efficaciously reduce alcohol use and anxiety, simultaneously. Such a drug would be very valuable given that alcohol use disorders are highly co-morbid with general anxiety disorders and post-traumatic stress disorders. Additionally, alcohol withdrawal induced anxiety is a major contributor to relapse and thus a bi-functional delta opioid drug would be a significantly better therapeutic option for patients suffering from alcohol use disorders than the currently available treatment options.