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

多巴胺（DA）对靶神经元的各种作用是通过典型的7-跨膜G 蛋白偶联受体（GPCR），通过G蛋白依赖性 机制等然而，现在广泛认识到，GPCR也可以通过免疫调节剂的能力发出信号。 衔接蛋白β抑制蛋白与支架信号传导复合物的结合不同于典型的G蛋白信号传导。 这些双信令模式可以实现通常所称的功能选择性或偏置 发信号。我们之前已经表明，多巴胺D2受体（D2 R），这是临床上的主要目标， 有效的抗精神病药物，通过参与一种 β抑制蛋白2/Akt/PP 2A/GSK 3 β信号复合物。在这个R37奖励的初始部分，我们使用了 遗传学、生物化学和药理学方法，以提供D2 R/β arrestin 2 信号传导在DA系统激活后的行为反应中是重要的。有趣的是，我们 在小鼠中使用β arrestin 2的神经选择性缺失发现， D2 R/β arrestin 2偏向工具化合物UNC 9994 A在纹状体中表现为拮抗剂，但在纹状体中表现为激动剂。 大脑皮层这些结果与皮质中GPCR激酶和β抑制蛋白2的较高水平相关， 纹状体和UNC 9994 A逆转认知/社交功能小鼠模型缺陷的能力。 这些结果表明，β arrestin 2/D2 R信号可能是一种不受重视的控制认知功能的手段。 和社会领域的行为。我们的R37延续应用程序的目标是使用遗传 以及我们开发的生化工具，如G蛋白或β抑制蛋白2偏好突变体D2 R， 参与这些行为域控制的类型特异性分子和生化机制。 我们的具体目标是：1）确定D2 R偏向信号对小鼠认知领域的影响 用偏向的D2 R突变体重建; 2）确定支持D2 R突变的分子和神经机制。 认知和社会影响，以及3）评估皮层中的D2 R偏置信号如何控制神经元 电生理学和影响下游的大脑回路，以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.