Akt/GSK-3 Signaling Cascade and the Actions of Dopamine

Akt/GSK-3 信号级联和多巴胺的作用

• 批准号: 9207482
• 负责人: Marc G. Caron
• 金额: $ 65.06万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-20 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9207482
• 关键词: Adaptor Signaling Protein; Address; Affect; Agonist; Antipsychotic Agents; Area; Atrophic; Award; Basic Science; Behavior; Behavior Control; Behavioral; Biochemical; Biological; Biological Neural Networks; Brain; Cellular Morphology; Cerebral cortex; Chronic; Clinical; Cognition; Cognitive; Cognitive Therapy; Complex; Corpus striatum structure; Disease; Dopamine; Dopamine D2 Receptor; Electrophysiology (science); Engineering; Fostering; Future; G Protein-Coupled Receptor Signaling; G protein coupled receptor kinase; G-Protein-Coupled Receptors; G-substrate; GTP-Binding Proteins; Genetic; Glycogen Synthase Kinase 3; Goals; Grant; Human; Impairment; Interneurons; Intervention; Ligands; Mediating; Messenger RNA; Molecular; Morphology; Mus; Mutant Strains Mice; NR1 gene; Neurons; Parvalbumins; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phase; Physical shape; Physiological; Physiology; Play; Population; Progress Reports; Property; Protein Phosphatase 2A Regulatory Subunit PR53; Pyramidal Cells; Quinpirole; Receptor Cell; Receptor Signaling; Regulation; Research; Resolution; Role; Signal Transduction; Signaling Protein; Slice; Social Behavior; Testing; Translating; Validation; Work; base; behavioral response; biochemical tools; brain circuitry; cell type; cognitive control; cognitive enhancement; cognitive function; cognitive reappraisal; dopamine system; in vivo; innovation; knock-down; mouse model; mutant; neuronal circuitry; neuropsychiatric disorder; neuropsychopharmacology; optogenetics; receptor; reconstitution; response; scaffold; small molecule; social; tool

The various actions of dopamine (DA) on target neurons are mediated via prototypical 7-transmembrane G protein-coupled receptors (GPCR) that couple to various effectors through G protein-dependent mechanisms. However, it is now widely appreciated that GPCRs can also signal through the ability of the adaptor protein βarrestin to scaffold signaling complexes that are distinct from canonical G protein signaling. These dual signaling modes may enable what is commonly referred to as functionally selective or biased signaling. We have shown before that the dopamine D2 receptor (D2R), which is the main target of clinically effective antipsychotics, mediates some of its physiological effects through engagement of a βarrestin2/Akt/PP2A/GSK3β signaling complex. During the initial portion of this R37 award, we have used genetic, biochemical, and pharmacological approaches to provide concrete evidence that D2R/βarrestin2 signaling is important in behavioral responses following activation of the DA system. Interestingly, we discovered using neuronally selective deletions of βarrestin2 in mice that an antipsychotic-like D2R/βarrestin2 biased tool compound UNC9994A behaved as an antagonist in the striatum but an agonist in the cortex. These results correlate with both higher levels of GPCR kinase and βarrestin2 in cortex versus striatum and the ability of UNC9994A to reverse deficits in a mouse model of cognitive/sociability functions. These results suggest that βarrestin2/D2R signaling may be an unappreciated means to control cognitive and social domains of behavior in vivo. The goals of our R37 continuation application are to use the genetic and biochemical tools we have developed, like G protein or βarrestin2 preferring mutant D2Rs, to identify cell type specific molecular and biochemical mechanisms involved in the control of these behavioral domains. Our Specific Aims are: 1) determine the impact of D2R biased signaling on cognitive domains in mice reconstituted with biased D2R mutants; 2) identify the molecular and neuronal mechanisms underpinning the cognitive and social effects and 3) assess how D2R biased signaling in the cortex controls neuronal electrophysiology and affects downstream brain circuits to control cognitive and sociability functions.

多巴胺（DA）对靶神经元的各种作用是通过典型的7跨膜G介导的 蛋白质偶联受体（GPCR），通过G蛋白依赖性伴侣伴随各种作用 机制。但是，现在广泛认为GPCR也可以通过 衔接蛋白βarrestin对脚手架信号传导复合物，与规范G蛋白信号不同。 这些双重信号模式可能会启用通常称为功能选择性或偏见的东西 信号。我们之前已经表明，多巴胺D2受体（D2R）是临床上的主要目标 有效的抗精神病药，通过参与来介导其某些物理作用 βarrestin2/akt/pp2a/gsk3β信号传导复合物。在此R37奖的最初部分中，我们使用了 遗传，生化和药物方法提供了具体证据表明D2R/βarRestin2 信号在激活DA系统后的行为响应中很重要。有趣的是，我们 在小鼠中使用βArrestin2的神经选择性缺失发现的抗精神病药 D2R/βarRestin2偏置工具化合物UNC994A在纹状体中表现为拮抗剂，但在 皮质。这些结果与皮层中较高水平的GPCR激酶和βarrestin2相关 纹状体和UNC9994A逆转的能力在认知/社交功能的小鼠模型中定义。 这些结果表明，βarrestin2/d2r信号传导可能是控制认知的一种手段 和体内行为的社会领域。我们R37持续应用的目标是使用通用 我们开发的生化工具，例如G蛋白或βarRestin2更喜欢突变型D2R，以鉴定细胞 涉及控制这些行为领域的特定分子和生化机制。 我们的具体目的是：1）确定D2R偏置信号对小鼠认知域的影响 用偏见的D2R突变体重构； 2）确定支撑的分子和神经元机制 认知和社会效应以及3）评估D2R在皮层中如何控制神经元的信号传导 电生理学并影响下游脑回路以控制认知和社交功能。