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: 7417483
• 负责人: Marc G. Caron
• 金额: $ 42.2万
• 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 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7417483
• 关键词: Address; Adenylate Cyclase; Animal Model; Animals; Area; Attention deficit hyperactivity disorder; Behavior; Behavioral; Biochemical; Biological Models; Brain; Brain Diseases; Calcineurin; Class; Condition; Corpus striatum structure; Coupled; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; DARPP 32; Development; Disease; Dissection; Dopamine; Dopamine Agonists; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Event; Family; Functional disorder; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Proteins; Gene Expression Regulation; Genetic; Gilles de la Tourette syndrome; Glycogen Synthase Kinase 3; Goals; Investigation; Lithium; Mediating; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Target; Molecular Weight; Mood Disorders; Mood stabilizers; Mus; Neurons; Neurotransmitters; Parkinson Disease; Pathway interactions; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Physiological; Population; Potassium Channel; Process; Production; Protein Dephosphorylation; Protein Isoforms; Receptor Signaling; Regulation; Research; Rewards; Role; Schizophrenia; Signal Pathway; Signal Transduction; Substantia nigra structure; System; Therapeutic Agents; Tissues; Ventral Tegmental Area; addiction; affective psychoses; dopamine system; dopaminergic neuron; in vivo; insight; novel therapeutics; pars compacta; protein phosphatase inhibitor-1; receptor; reconstitution; reconstruction; research study; response; tool

DESCRIPTION (provided by applicant): Dopamine (DA) is a monoaminergic neurotransmitter that has been implicated in multiple disorders such as Parkinson's disease, schizophrenia, attention deficit hyperactivity disorder, Tourette syndrome, addiction and affective disorders. At the cellular level the various actions of DA on target neurons are mediated via a family of 5 distinct G protein-coupled receptors. The D1-like (D1 and D5) receptors are mostly coupled to activation of the cAMP signaling cascade through the G protein Gs whereas the D2-like receptors (D2, D3 and D4) signal through Gi/Go and can inhibit the cAMP cascade. D2-like receptors also modulate Ca2+ and K + channels and can engage other signals such as MAP kinase pathways. Whereas most classical animal and cellular studies have focused on cAMP mediating the actions of DA, the applicability or potential contribution of other signaling pathways is still not fully understood. Recent investigations in mice have revealed that behavioral manifestations of elevated DA tone in the brain in response to genetic or pharmacological manipulations and the ability of lithium to antagonize these behaviors correlate with modulation of the Akt/GSK-3 signaling pathway in a cAMP-independent fashion. The overall objective of the proposed research is to define the molecular and cellular mechanisms that contribute to these processes with the goal of better understanding physiological and pathological conditions. Studies will be conducted both in cellular systems as well as in normal and genetically modified animal models. Aim 1: We will attempt to characterize the mechanisms by which dopamine regulate Akt/GSK-3 signaling. This will include determining which of the DA receptors and molecular signaling intermediates engage the Akt pathway and reconstitution of those interactions in cellular systems. Aim 2: We will address characterization of the molecular targets of GSK-3 that mediate responses to DA. Aim 3: These proposed experiments will examine the role of Akt/GSK-3 in DA-associated behaviors, such as those modeling affective and psychotic disorders, in animals carrying tissue-specific genetic deletion of various GSK-3 isoforms. Results from these studies should broaden our understanding of the cellular and molecular mechanisms mediating the actions of DA in normal and pathophysiological conditions and provide insight into potential novel therapeutic approaches for 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，与多种疾病有关，例如帕金森病、精神分裂症、注意力缺陷多动障碍、抽动秽语综合征、成瘾和情感障碍。在细胞水平上，DA 对靶神经元的各种作用是通过 5 个不同的 G 蛋白偶联受体家族介导的。 D1 样受体（D1 和 D5）主要通过 G 蛋白 Gs 与 cAMP 信号级联的激活偶联，而 D2 样受体（D2、D3 和 D4）通过 Gi/Go 发出信号并可以抑制 cAMP 级联。 D2 样受体还调节 Ca2+ 和 K + 通道，并可以参与其他信号，例如 MAP 激酶途径。尽管大多数经典的动物和细胞研究都集中于 cAMP 介导 DA 的作用，但其他信号通路的适用性或潜在贡献仍未完全了解。最近对小鼠的研究表明，大脑中因遗传或药理学操作而出现的 DA 张力升高的行为表现以及锂拮抗这些行为的能力与以不依赖于 cAMP 的方式调节 Akt/GSK-3 信号通路相关。拟议研究的总体目标是定义有助于这些过程的分子和细胞机制，以更好地了解生理和病理条件。研究将在细胞系统以及正常和转基因动物模型中进行。目标 1：我们将尝试描述多巴胺调节 Akt/GSK-3 信号传导的机制。这将包括确定哪些 DA 受体和分子信号传导中间体参与 Akt 途径并重建细胞系统中的这些相互作用。目标 2：我们将解决介导 DA 反应的 GSK-3 分子靶点的表征。目标 3：这些拟议的实验将检查 Akt/GSK-3 在 DA 相关行为中的作用，例如在携带各种 GSK-3 同工型组织特异性遗传缺失的动物中模拟情感和精神障碍。这些研究的结果应拓宽我们对正常和病理生理条件下介导 DA 作用的细胞和分子机制的理解，并为各种精神疾病的潜在新治疗方法提供见解。