Beta-catenin modulates dopamine dependent signal transduction and behavior.

β-连环蛋白调节多巴胺依赖性信号转导和行为。

• 批准号: 8416819
• 负责人: Joshua Clair Snyder
• 金额: $ 5.39万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-08 至 2014-08-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416819
• 关键词: AKT inhibition; Affect; Alleles; Anatomy; Antipsychotic Agents; Anxiety; Anxiety Disorders; Attention deficit hyperactivity disorder; Attenuated; Basal Ganglia; Behavior; Behavioral; Biochemical; Biochemistry; Biogenic Amines; Brain; Brain region; Breeding; Cell Nucleus; Cells; Complex; Corpus striatum structure; Coupling; Cyclic AMP; DRD2 gene; Dendrites; Development; Disease; Dopamine; Drug usage; Effectiveness; Engineering; Event; Exons; Family; Fellowship; Fractionation; Fright; Future; G-Protein-Coupled Receptors; GTP-Binding Proteins; Generations; Genetic; Genetic Recombination; Huntington Disease; Intervention; Knock-out; Knockout Mice; Knowledge; Learning; Lithium Chloride; Location; Locomotion; Manuscripts; Mediating; Mediator of activation protein; Mental Depression; Mental disorders; Midbrain structure; Modality; Molecular; Mood stabilizers; Morphology; Mus; Neurons; Neurotransmitters; Parkinson Disease; Pathway interactions; Patient Care; Physiological; Population; Prevalence; Process; Production; Protein Phosphatase 2A Regulatory Subunit PR53; Protein phosphatase; Proteins; Proto-Oncogene Proteins c-akt; Psychotic Disorders; Psychotropic Drugs; Quality of life; Reporter; Reporting; Research; Research Proposals; Role; Schizophrenia; Second Messenger Systems; Signal Transduction; Site; Slice; Stimulus; Substantia nigra structure; Syndrome; System; Testing; Thalamic structure; Transgenic Organisms; Ventral Tegmental Area; Work; arrestin 2; atypical antipsychotic; base; beta catenin; cell type; dopamine transporter; dopaminergic neuron; drug of abuse; genetic analysis; improved; insight; monoamine; motor control; mouse Cre recombinase; mouse model; nervous system disorder; neural circuit; next generation; novel; pars compacta; protein complex; psychologic; second messenger; selective expression; seven-transmembrane G-protein-coupled receptor; transmission process

DESCRIPTION (provided by applicant): The basal ganglia is a critical regulator of a myriad of processes in the brain including motor control and behavior. This system is divided into several nuclei based upon anatomical location and connectivity, the largest of which is referred to as the striatum. The predominant neuronal cell type of the striatum is the inhibitory medium spiny neuron (MSN), which form the direct and indirect pathway based upon functional differences in anatomy and biochemistry. Biochemically, both MSN populations are innervated by dopaminergic neurons from the midbrain and respond to the monoamine neurotransmitter dopamine. However, dopamine signals through two families of G-protein coupled receptors (GPCR)s referred to as D1 and D2 GPCRs, which are selectively expressed in MSNs of the direct or indirect pathway, respectively. D1 and D2 GPCRs can be further distinguished biochemically by their respective positive or negative coupling to the generation of the downstream second messenger cAMP. Perturbations to dopamine signal transduction are implicated in a number of mental health disorders including anxiety, schizophrenia, depression, and attention deficit hyperactivity disorder. Given the prevalence of these disorders world-wide, studies to elucidate the basic signal transduction mechanisms responsible for dopamine signal transduction are necessary to develop more effective strategies of pharmacological intervention. Recent work has identified a G-protein independent modality of dopamine signaling that regulates behavior. This pathway is dependent upon 2-arrestin-2 mediated complex formation of AKT, GSK-32, and protein phosphatase 2 (PP2A). Dopamine stimulus promotes formation of this complex, resulting in activation of GSK-32 through inhibition of AKT by PP2A, and activation of dopamine dependent behavior. Currently, downstream targets of GSK-32 in this signaling paradigm have not been identified. The exciting finding that clinically effective antipsychotics target 2-arrestin- 2 mediated dopamine signaling provides further justification for delineating the downstream effectors of this pathway. Given the role for 2-catenin as a primary target of GSK-32 action and numerous reports suggesting that 2-catenin may be a downstream effector molecule necessary for the efficacy of psychotropic drugs we propose to test the hypothesis that that dopamine signaling and the actions of psychotropic drugs are mediated in part by 2-catenin. This hypothesis will be tested by interrogation of two specific aims that utilize a comprehensive genetic analysis to: 1) Characterize 2-catenin signaling in mouse models of hyper- dopaminergia and hypo-dopaminergia and 2) Determine the necessity for 2-catenin signaling in mediating dopamine dependent signaling and the actions of psychotropic drugs using floxed alleles of 2-catenin, which attenuate or potentiate 2-catenin signaling. Completion of this proposal will provide further insight into dopamine dependent signaling and behaviors. Ultimately, this may provide a framework for the development of more efficacious treatments of neurological disease.

描述（由申请人提供）：基底神经节是大脑中包括运动控制和行为在内的无数过程的关键调节器。该系统根据解剖位置和连通性分为几个核，其中最大的被称为纹状体。纹状体的主要神经细胞类型是抑制性介质棘神经元（MSN），基于解剖学和生物化学的功能差异，它们形成了直接和间接的通路。从生物化学角度来看，这两个MSN群体都受来自中脑的多巴胺能神经元的支配，并对单胺类神经递质多巴胺有反应。然而，多巴胺信号通过两个g蛋白偶联受体（GPCR）家族，即D1和D2 GPCR，分别在直接或间接途径的msn中选择性表达。D1和D2 gpcr可以通过它们各自与下游第二信使cAMP的正偶联或负偶联进一步区分。多巴胺信号转导的扰动与许多心理健康障碍有关，包括焦虑、精神分裂症、抑郁症和注意缺陷多动障碍。鉴于这些疾病在世界范围内的普遍性，研究阐明多巴胺信号转导的基本信号转导机制对于制定更有效的药物干预策略是必要的。最近的工作已经确定了一种不依赖于g蛋白的多巴胺信号模式，可以调节行为。该途径依赖于2-arrestin-2介导的AKT、GSK-32和蛋白磷酸酶2 （PP2A）复合物的形成。多巴胺刺激促进该复合物的形成，通过PP2A抑制AKT激活GSK-32，激活多巴胺依赖行为。目前，GSK-32在这种信号传导模式中的下游靶点尚未确定。临床有效的抗精神病药物靶向2-抑制素- 2介导的多巴胺信号，这一令人兴奋的发现为描述这一途径的下游效应提供了进一步的理由。考虑到2-catenin作为GSK-32作用的主要靶点的作用，以及大量报道表明2-catenin可能是精神药物疗效所必需的下游效应分子，我们建议验证多巴胺信号传导和精神药物作用部分由2-catenin介导的假设。这一假设将通过对两个特定目标的询问来验证，这两个目标利用全面的遗传分析来：1)表征高多巴胺能和低多巴胺能小鼠模型中的2-catenin信号传导；2)确定2-catenin信号传导在介导多巴胺依赖信号传导中的必要性，以及使用2-catenin的受限等位基因的精神药物的作用，这些等位基因可以减弱或增强2-catenin信号传导。这一建议的完成将进一步深入了解多巴胺依赖的信号和行为。最终，这可能为开发更有效的神经系统疾病治疗方法提供一个框架。