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; 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.

项目摘要/摘要 G蛋白偶联受体（GPCR）长期以来一直是制药公司的最爱目标 众多疾病的治疗易于进入和无处不在。主要的 GPCR的信号传输途径是通过Namesaki G蛋白途径和通过相互作用 与β-arrestin连接支架。包括我自己在内的几个研究小组已经确定了G- 蛋白质和β-arrestin都可以独特地调节行为类型。发现毒品作用的发现 在GPCR上可以存在所谓的功能选择性[即仅激活一条途径，而不是另一种途径] 为开发信号有偏见的药物而产生的新机会较少。 G蛋白和β-arre蛋白主要提供信号级联反应的差异，而一小部分 酶模棱两可在这两种途径中扮演角色。特别感兴趣的是有丝分裂原活化蛋白 激酶“ ERK”（细胞外信号调节激酶）。 ERK功能和功能障碍已链接到 许多疾病和疾病，例如癌症，抑郁和药物成瘾。有许多研究 进行了研究，研究了G蛋白和β-arre蛋白如何调节简单细胞中的ERK活性 型号。但是，由于缺乏特定工具，很难确定G蛋白如何 介导的和β-arrestin介导的ERK激活分别有助于行为的调节。 特别是ERK激活的总量是背后的驱动力，这是很感兴趣的 生理效应，或激活机制（G蛋白与β-arrest蛋白）是否重要。 最近的药理学进步现在使我们能够提出实验，以使 在行为测定中解剖G蛋白和β-arrestin ERK激活。对于此建议，我们将使用 作用于三角洲阿片受体的G蛋白和β-arre依的偏置药物，并利用创新 解决我们的研究问题的化学生成方法。我们先前研究三角洲的研究 受体表明，该受体处的G蛋白偏置药物可以减少酒精的使用，而 那些激活ERK的三角洲阿片类药物减少了动画。完成这项研究后，我们将能够 解决有关信号偏向ERK激活的基本问题，与酒精使用有关 类似动画的行为。更重要的是，我们将能够描述“如何偏见”三角洲阿片类药物接收器 药物必须是以及应如何激活以有效减少的ERK /多少erk 饮酒和焦虑，简单。鉴于酒精的使用，这种药物将非常有价值 疾病与普通焦虑症和创伤后应激障碍相关。 此外，戒酒诱导的动画是继电器的主要因素，因此是双功能 对于患有酒精的患者而言，三角洲阿片类药物将是一个更好的治疗选择 疾病比当前可用的治疗方案。