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

多巴胺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)通过依赖G蛋白与多种效应器偶联 机械装置。然而，现在人们普遍认识到，GPCR还可以通过 适配子蛋白β与支架信号复合体形成不同于典型G蛋白信号的复合体。 这些双重信令模式可以实现通常所说的功能选择性或偏向 发信号。我们已经证明，多巴胺D2受体(D2R)是临床治疗的主要靶点。 有效的抗精神病药物，通过参与一种 β抑制蛋白2/Akt/Pp2A/Gsk3β信号复合体。在这个R37奖项的初始阶段，我们使用了 遗传学、生化和药理学方法提供D2R/β拦阻蛋白2的具体证据 信号在DA系统激活后的行为反应中很重要。有趣的是，我们 在小鼠中发现使用神经选择性缺失β拦阻蛋白2的抗精神病药物 D2R/β阻滞素2偏向工具化合物UNC9994A在纹状体中表现为拮抗剂，在纹状体中表现为激动剂 大脑皮层。这些结果与皮质中较高水平的GPCRK和β抑制蛋白2有关。 纹状体和UNC9994A逆转小鼠认知/社交功能缺陷的能力。 这些结果表明，β抑制蛋白2/D2R信号可能是一种未被认可的控制认知的手段 以及活体内行为的社会领域。我们的R37延续应用程序的目标是使用基因 以及我们开发的生化工具，如G蛋白或β抑制蛋白2，更喜欢突变的D2Rs，以识别细胞 类型特定的分子和生化机制参与这些行为领域的控制。 我们的具体目标是：1)确定D2R偏向信号对小鼠认知领域的影响 与偏向的D2R突变体重组；2)确定支持D2R突变体的分子和神经元机制 认知和社会影响以及3)评估大脑皮质中D2R偏向信号如何控制神经元 电生理，并影响下游的大脑回路，控制认知和社交功能。

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.