Role of beta arrestin 2 in neurotransmission

G蛋白偶联受体（GPCRs）代表参与神经传递调节的最重要的细胞表面受体家族。 GPCR被认为通过激活异源三聚体G蛋白来调节细胞信号传导。 然而，GPCR也已显示通过形成由信号分子和支架蛋白β-抑制蛋白组成的信号复合物（信号组）来发挥其作用。 我们最近证明，这种β-arrestin信号组介导体内多巴胺受体的一些作用。 这种复合物在小鼠纹状体中的破坏导致多巴胺对信号分子Akt和GSK 3的调节丧失，并且在缺乏β抑制蛋白2的小鼠中对多巴胺能药物的行为反应降低。 拟议的研究方案的目的是进一步研究β-arrestin信号复合物对Akt和GSK 3的调节，并确定调节β-arrestin信号复合物形成的其他神经递质/受体系统。 这项研究将涉及使用不同的GPCR响应神经递质，以评估这些受体对β-arrestin信号复合物形成的参与。 随后，将使用β抑制蛋白敲除小鼠在体内评价这些发现的生理相关性。 β-arrestin介导的GPCR信号可能代表了一种新的神经传递机制，更好地了解其机制和体内相关性可能会导致更好地了解基本的神经生物学过程，如神经发育和成年哺乳动物大脑的正常功能。

G protein coupled receptors (GPCRs) represents the most important family of cell surface receptors involved in the regulation of neurotransmission. GPCRs are believed to regulate cell signaling trough activation of heterotrimeric G proteins. However, GPCRs have also been shown to exert their action through the formation of signaling complexes (signalomes) composed of signaling molecules and the scaffolding proteins beta-arrestins. We recently demonstrated that such a beta-arrestin signalome mediates some effects of dopamine receptor in vivo. Disruption of this complex in the mouse striatum results in a loss of regulation of signaling molecules Akt and GSK3 by dopamine and in reduced behavioral responses to dopaminergic drugs in mice lacking beta arrestin 2. The proposed research protocol has for objectives to examine further the regulation of Akt and GSK3 by beta-arrestin signaling complexes and to identify other neurotransmitter/receptor systems regulating the formation of beta-arrestin signaling complexes. This research will involve the use of different GPCR responding to neurotransmitters to evaluate the involvement of these receptors on the formation of beta-arrestin signaling complexes. Subsequently the physiological relevance of these findings will be evaluated in vivo using beta arrestin knockout mice. Beta-arrestin mediated signaling by GPCR may represent a general new mechanism of neurotransmission and a better understanding of its mechanism and in vivo relevance may lead to a better understanding of basic neurobiological processes such as neurodevelopment and the normal functions of the adult mammalian brain.