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

Akt/GSK-3 信号级联和多巴胺的作用

基本信息

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
项目类别：
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

项目摘要

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 介导的蛋白偶联受体 (GPCR) 通过 G 蛋白依赖性与各种效应器偶联然而，现在人们普遍认识到 GPCR 也可以通过 GPCR 的能力发出信号。接头蛋白 β 抑制蛋白与支架信号传导复合物的连接不同于典型的 G 蛋白信号传导。这些双重信号模式可以实现通常所说的功能选择性或偏向性我们之前已经证明了多巴胺D2受体（D2R），这是临床上的主要靶点。有效的抗精神病药，通过参与介导其一些生理作用 βarrestin2/Akt/PP2A/GSK3β 信号复合物在 R37 奖项的初始部分，我们使用了。遗传、生化和药理学方法提供 D2R/βarrestin2 的具体证据信号传导对于 DA 系统激活后的行为反应非常重要。通过在小鼠中神经元选择性删除 βarrestin2 发现，一种抗精神病药样药物 D2R/βarrestin2 偏向工具化合物 UNC9994A 在纹状体中表现为拮抗剂，但在纹状体中表现为激动剂这些结果与皮质中较高水平的 GPCR 激酶和 βarrestin2 相关。纹状体和 UNC9994A 逆转小鼠模型认知/社交功能缺陷的能力。这些结果表明 βarrestin2/D2R 信号传导可能是一种未被重视的控制认知的手段。我们 R37 延续应用的目标是利用基因。以及我们开发的生化工具，例如 G 蛋白或 βarrestin2 偏好突变型 D2R，以识别细胞参与控制这些行为领域的特定分子和生化机制。我们的具体目标是：1) 确定 D2R 偏向信号传导对小鼠认知领域的影响 2）确定支撑的分子和神经机制认知和社会影响，3) 评估皮层中 D2R 偏向信号如何控制神经电生理学并影响下游大脑回路以控制认知和社交功能。