A role for beta-arrestins in mGluR-dependent plasticity

描述（由申请人提供）：β -阻滞蛋白是与七个跨膜受体（即gpcr）的羧基末端尾部相互作用的细胞质蛋白，在脱敏、内化和支架其他蛋白中发挥作用，这些蛋白启动细胞内信号级联，独立于G蛋白的激活。由于后一种非规范信号传导模式是一种相对较新的发现，因此β -阻滞蛋白在大多数gpcr下游转导不依赖于G蛋白的信号传导的程度尚不清楚。代谢性谷氨酸受体（mGluRs）代表了这样一个受体家族，与β -抑制素的关系在很大程度上是未知的。在本项目中，我们将验证I组mGluRs （mGluR1和mGluR5）有可能激活b-阻滞蛋白依赖的信号通路，并且通过非g蛋白介导的机制进行信号传导在一定程度上是海马中mglur依赖的突触可塑性形式的基础。在Specific Aim 1中，我们将确定哺乳动物大脑中哪一组mglur1与b-arrestin-1和-2相关，并研究mglur1依赖的海马苔藓纤维- CA3锥体神经元突触的可塑性是如何通过与一种或两种b-arrestins相关而改变的。在Specific Aim 2中，我们将阐明苔藓纤维突触中mglur1依赖性可塑性的信号级联。在Specific Aim 3中，我们将测试b-阻滞蛋白在1组mglur依赖的Schaffer侧枝- CA1锥体神经元突触可塑性中的作用。这些实验有可能揭示新的信号通路在海马突触可塑性中的意想不到的贡献，这些通路是mGluRs的下游，但独立于典型的G蛋白过程。β -抑制蛋白依赖信号的存在也将支持mGluRs偏倚配体的潜在发展。因此，这项研究的结果可以为I组mGluRs的治疗靶向新策略提供见解，近年来，许多神经病理学都在追求这种新策略。

DESCRIPTION (provided by applicant): Beta-arrestins are cytosolic proteins that interact with the carboxy-terminal tails of seven-transmembrane receptors (i.e., GPCRs) and play a role in desensitization, internalization, and scaffolding other proteins that initiate intracellular signalng cascades independent of G protein activation. Because the latter non-canonical signaling mode is a relatively new discovery, the extent to which beta-arrestins transduce G protein-independent signaling downstream of most types of GPCRs is unknown. Metabotropic glutamate receptors (mGluRs) represent one such family of receptors with a largely uncharacterized relationship to beta-arrestins. In this project, we will test the hypothesis that group I mGluRs (mGluR1 and mGluR5) have the potential to activate b-arrestin-dependent signaling pathways, and that signaling through non-G protein-mediated mechanisms in part underlie mGluR-dependent forms of synaptic plasticity in the hippocampus. In Specific Aim 1, we will determine which group I mGluRs associate with b-arrestin-1 and -2 in the mammalian brain and examine how an mGluR1-dependent form of hippocampal plasticity at mossy fiber - CA3 pyramidal neuron synapses is altered by association with one or both b-arrestins. In Specific Aim 2, we will elucidate which signaling cascades underlie mGluR1-dependent plasticity at mossy fiber synapses. In Specific Aim 3, we will test the role of b-arrestins in a group I mGluR-dependent plasticity at Schaffer collateral - CA1 pyramidal neuron synapses. These experiments have the potential to reveal an unexpected contribution by novel signaling pathways, those downstream of mGluRs but independent of canonical G protein processes, in synaptic plasticity in the hippocampus. The existence of beta-arrestin-dependent signaling would also support the potential development of biased ligands for mGluRs. The outcomes of this study could therefore yield insight into new strategies for therapeutic targeting of group I mGluRs, which in recent years has been pursued for a number of neuropathologies.