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

酒精使用和焦虑障碍中的 G 蛋白、β-抑制蛋白和 ERK 信号传导

• 批准号: 9766989
• 负责人: Richard M. van Rijn
• 金额: $ 33.83万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-10 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766989
• 关键词: Address; Adverse effects; Agonist; Alcohol consumption; Alcohol withdrawal syndrome; Amygdaloid structure; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Arrestins; Behavior; Behavioral Assay; Biological Assay; Brain; Brain region; Cell model; Corpus striatum structure; Data; Development; Disease; Dissection; Dorsal; Drug Addiction; Drug Receptors; Drug Targeting; Drug usage; Environment; Enzymes; Event; Exhibits; Extracellular Signal Regulated Kinases; Fright; Functional disorder; Future; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Hippocampus (Brain); Individual; Intake; Knockout Mice; Knowledge; Light; Link; Malignant Neoplasms; Measures; Mediating; Mental Depression; Mitogen-Activated Protein Kinases; Moods; Mus; Muscarinics; Mutate; Neurologic; Opioid; Opioid Receptor; Opioid agonist; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacological Treatment; Pharmacology; Phosphorylation; Phosphotransferases; Physiological; Play; Post-Traumatic Stress Disorders; Property; Proteins; Relapse; Research; Research Proposals; Role; Route; Signal Pathway; Signal Transduction; Source; Stress; Structure; Therapeutic; addiction; alcohol exposure; alcohol use disorder; anxiety-like behavior; behavioral response; beta-arrestin; delta opioid receptor; designer receptors exclusively activated by designer drugs; driving force; drug development; experimental study; extracellular; inhibitor/antagonist; innovation; insight; interest; kappa opioid receptors; neuropsychiatric disorder; novel; precision medicine; protein B; receptor; reduced alcohol use; scaffold; tool; withdrawal-induced anxiety

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.

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目标 治疗多种疾病，因为它们很容易获得并且普遍存在。 GPCR 的信号转导途径是通过同名的 G 蛋白途径并通过相互作用 包括我自己的研究小组在内的几个研究小组已经确定了 G- 蛋白质和β-抑制蛋白可以各自独特地调节行为类型。 at GPCR 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） 为开发副作用较少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，但一小部分 酶在这两种途径中都发挥着模糊的作用，特别令人感兴趣的是丝裂原激活蛋白。 激酶“ERK”（细胞外信号调节激酶）与 ERK 功能和功能障碍有关。 许多研究表明，癌症、抑郁症和毒瘾等许多疾病和病症。 进行了研究 G 蛋白和 β-抑制蛋白如何调节简单细胞中的 ERK 活性 然而，由于缺乏特定的工具，建立 G 蛋白如何生成变得更加困难。 介导的 ERK 激活和 β-arrestin 介导的 ERK 激活分别有助于行为的调节。 特别值得关注的是 ERK 激活总量是否是 ERK 激活背后的驱动力。 生理效应，或者激活机制（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，使 在行为分析中，我们将使用 G 蛋白和 β-arrestin ERK 激活的剖析。 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 我们之前的研究调查了 delta 阿片类药物。 受体表明，针对该受体的 G 蛋白偏向药物可以减少饮酒，而 那些激活 ERK 的 delta 阿片类药物可以减少焦虑。 解决与饮酒相关的信号偏向 ERK 激活的基本问题，以及 更重要的是，我们将能够描述 δ 阿片受体的“偏见程度”。 药物必须是以及它应该能够激活多少 ERK 才能有效地减少 考虑到饮酒和焦虑，这种药物将非常有价值。 障碍与一般性焦虑症和创伤后应激障碍高度共存。 此外，酒精戒断引起的焦虑是复发的主要原因，因此具有双重功能。 对于酗酒患者来说，δ阿片类药物将是一种更好的治疗选择 疾病比目前可用的治疗方案。