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

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对目标神经元的各种作用是通过典型的7-跨膜G蛋白偶联受体介导的，该受体通过G蛋白依赖机制偶联各种效应器。我们之前的工作已经证明，在纹状体中，DA D2受体（D2R）通过Akt/GSK3信号通路以不依赖G蛋白的方式通过a ？-阻滞蛋白2/Akt/PP2A信号复合物导致Akt的抑制和随之而来的GSK3的激活。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和精神分裂症或躁狂等疾病中发挥重要作用。临床有效的结合D2Rs的抗精神病药物显示出与？-抑制素2介导的途径，心境稳定剂锂通过抑制？-阻滞蛋白2/Akt/PP2A信号复合物。尽管这些令人兴奋的细胞结果，这一途径在体内的功能后果尚不清楚。本研究的总体目标是建立一系列动物模型，在这些模型中，D2Rs下游通路的功能可以在不同水平上精确地研究？-arrestin 2。目标1：我们将研究GSK3的作用。然后呢?-catenin通过在纹状体输出通路的突触后表达D1R和d2r的神经元中选择性地操纵DA的作用。目标2：我们将确定？通过选择性地在相同的突触后神经元中失活和恢复其功能来抑制- artin2。目标3：最后，我们将设计有选择地表达野生型或D2Rs的小鼠系，这些D2Rs可以通过G蛋白或a ？- 2依赖机制在这些突触后神经元中。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的D2R信号传导机制如何在纹状体中传导DA的作用提供独特的理解，我们的结果将为开发新的治疗药物提供新的见解。

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.