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: 8042192
• 负责人: Marc G. Caron
• 金额: $ 62.13万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-17 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8042192
• 关键词: Affect; Animal Model; Animals; Antipsychotic Agents; Arrestins; Attention; Attention deficit hyperactivity disorder; Attenuated; Behavior; Behavioral; Binding; Biochemical; Biological; Biological Models; Biological Process; Brain; Cells; Cognition; Complex; Corpus striatum structure; Development; Disease; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Drug Delivery Systems; Efferent Pathways; Emotions; Engineering; Etiology; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Proteins; Generations; Genetic; Gilles de la Tourette syndrome; Glycogen Synthase Kinase 3; Goals; Heterotrimeric GTP-Binding Proteins; Human; Huntington Disease; Hyperactive behavior; Investigation; Lead; Lithium; Locomotion; Manic; Mediating; Mental disorders; Mood Disorders; Mood stabilizers; Mus; Neuromodulator; Neurons; Neurotransmitters; Outcome; Parkinson Disease; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phosphorylation; Phosphotransferases; Population; Process; Protein Phosphatase 2A Regulatory Subunit PR53; Psychiatry; Receptor Signaling; Regulation; Research; Rewards; Role; Schizophrenia; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Stimulus; Symptoms; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Validation; Work; addiction; arrestin 2; base; cell type; dopamine system; in vivo; indexing; insight; loss of function; mutant; nervous system disorder; novel; novel therapeutics; postsynaptic; receptor; receptor coupling; receptor-mediated signaling; response; scaffold; selective expression; transmission process

DESCRIPTION (provided by applicant): Dopamine (DA) is a monoaminergic neurotransmitter that has been implicated in multiple neurological and psychiatric disorders in the CNS. The various actions of DA on target neurons are mediated via prototypical 7-transmembrane G protein-coupled receptors that couple to various effectors through G protein-dependent mechanisms. Our previous work has demonstrated that in the striatum, DA D2 receptors (D2R) mediate some of their actions through the Akt/GSK3 signaling pathway in a G protein-independent fashion via formation of a ?-arrestin 2/Akt/PP2A signaling complex leading to inhibition of Akt and the consequent activation of GSK3. Recent investigations in animals and humans have suggested an important role for the Akt/GSK3 signaling pathway in behavioral manifestations of elevated DA tone and in conditions like schizophrenia or mania. Clinically effective antipsychotic drugs that bind D2Rs show a high propensity to engage the ?-arrestin 2-mediated pathway, and the mood stabilizer lithium interferes with this pathway by inhibiting the stability of the ?-arrestin 2/Akt/PP2A signaling complex. Despite these exciting cellular results, the functional consequences of this pathway in vivo are poorly understood. The overall objective of this research is to generate a series of animal models in which the functioning of the pathway downstream of D2Rs can be precisely investigated at different levels downstream of ?-arrestin 2. Aim 1: We will examine the role of GSK3? and ?-catenin in the actions of DA by selectively manipulating them in postsynaptic D1R- and D2R-expressing neurons of the striatal efferent pathways. Aim 2: We will determine the contribution of ?-arrestin 2 by selectively inactivating and rescuing its function in the same postsynaptic neurons. Aim 3: Finally, we will engineer mouse lines that selectively express either wild type or D2Rs that can selectively couple through either a G protein- or a ?-arrestin 2-dependent mechanism in these same postsynaptic neurons. We anticipate that the biochemical, cell biological and behavioral analyses of these animal models will provide a unique understanding of how this novel D2R signaling mechanism transduces the actions of DA in striatum and that our results will provide novel insights into the development of new therapeutic agents. PUBLIC HEALTH RELEVANCE: The neurotransmitter dopamine has been implicated in multiple psychiatric disorders including Parkinson's and Huntington's diseases, schizophrenia, attention deficit-hyperactivity disorder, Tourette syndrome, mania, addiction and affective disorders. We have previously identified a novel signaling mechanism transduced through dopamine D2-like receptors. Since these receptors are primary targets for antipsychotic drugs, and because these drugs have wide application in psychiatry, this new signaling pathway may be important both in the etiology of these conditions and in their therapeutic management. The targeting of components in this pathway through generation of genetically-modified mice should clarify the in vivo role of this pathway under normal and pathophysiological actions of dopamine transmission and provide unique insights into the development of novel pharmacotherapies to treat the various psychiatric conditions.

描述（由申请人提供）：多巴胺（DA）是一种单胺能神经递质，与中枢神经系统的多种神经和精神疾病有关。 DA 对靶神经元的各种作用是通过典型的 7 次跨膜 G 蛋白偶联受体介导的，这些受体通过 G 蛋白依赖性机制与各种效应器偶联。我们之前的工作表明，在纹状体中，DA D2 受体 (D2R) 通过形成 β-arrestin 2/Akt/PP2A 信号复合物，以不依赖于 G 蛋白的方式通过 Akt/GSK3 信号通路介导其某些作用，从而抑制 Akt 并随后激活 GSK3。最近对动物和人类的研究表明，Akt/GSK3 信号通路在 DA 音调升高的行为表现以及精神分裂症或躁狂症等疾病中发挥着重要作用。结合 D2R 的临床有效抗精神病药物表现出高度参与 β-arrestin 2 介导途径的倾向，而情绪稳定剂锂通过抑制 β-arrestin 2/Akt/PP2A 信号复合物的稳定性来干扰该途径。尽管有这些令人兴奋的细胞结果，但该途径在体内的功能后果却知之甚少。本研究的总体目标是建立一系列动物模型，在这些模型中，可以在 β-arrestin 2 下游的不同水平上精确研究 D2R 下游通路的功能。 目标 1：我们将研究 GSK3 的作用？和β-连环蛋白通过选择性地操纵纹状体传出通路的突触后表达 D1R 和 D2R 的神经元来参与 DA 的作用。目标 2：我们将通过选择性失活和挽救相同突触后神经元中的 β-arrestin 2 功能来确定其贡献。目标 3：最后，我们将设计选择性表达野生型或 D2R 的小鼠品系，这些小鼠品系可以在这些相同的突触后神经元中通过 G 蛋白或 β-抑制蛋白 2 依赖性机制选择性偶联。我们预计这些动物模型的生化、细胞生物学和行为分析将为这种新型 D2R 信号传导机制如何转导纹状体中 DA 的作用提供独特的理解，并且我们的结果将为新治疗药物的开发提供新的见解。 公共健康相关性：神经递质多巴胺与多种精神疾病有关，包括帕金森病和亨廷顿病、精神分裂症、注意力缺陷多动障碍、抽动秽语综合症、躁狂症、成瘾和情感障碍。我们之前已经发现了一种通过多巴胺 D2 样受体转导的新型信号传导机制。由于这些受体是抗精神病药物的主要靶点，并且这些药物在精神病学中具有广泛的应用，因此这种新的信号传导途径可能在这些疾病的病因学及其治疗管理中都很重要。通过产生转基因小鼠来靶向该途径中的成分，应阐明该途径在多巴胺传递的正常和病理生理作用下的体内作用，并为治疗各种精神疾病的新型药物疗法的开发提供独特的见解。