A role for beta-arrestins in mGluR-dependent plasticity

描述（由申请人提供）：β-抑制蛋白是与七跨膜受体（即，GPCR），并在脱敏、内化和支架化其他蛋白质中发挥作用，这些蛋白质启动不依赖于G蛋白活化的细胞内信号级联。由于后者的非经典信号模式是一个相对较新的发现，在何种程度上β-arrestins β-GPCRs蛋白的非依赖性信号下游的大多数类型的GPCRs是未知的。代谢型谷氨酸受体（mGluRs）代表了这样一个受体家族，与β-抑制蛋白的关系在很大程度上尚未表征。在这个项目中，我们将测试的假设，即组I mGluR（mGluR 1和mGluR 5）有可能激活b-抑制蛋白依赖的信号通路，并通过非G蛋白介导的机制，部分基础mGluR依赖形式的突触可塑性在海马信号。在具体目标1中，我们将确定哪些组I mGluRs与哺乳动物脑中的b-抑制蛋白-1和-2相关，并研究mGluR 1依赖形式的苔藓纤维-CA 3锥体神经元突触的海马可塑性如何通过与一种或两种b-抑制蛋白相关而改变。在具体目标2中，我们将阐明mGluR 1依赖的可塑性苔藓纤维突触的信号级联的基础。在具体目标3中，我们将测试b-抑制蛋白在谢弗侧支-CA 1锥体神经元突触的I组mGluR依赖性可塑性中的作用。这些实验有可能揭示一个意想不到的贡献，新的信号通路，那些下游的mGluRs，但独立的典型G蛋白过程，在海马突触可塑性。β-抑制蛋白依赖性信号传导的存在也将支持mGluRs的偏向性配体的潜在开发。因此，本研究的结果可以深入了解I组mGluRs治疗靶向的新策略，近年来，I组mGluRs已被用于许多神经病理学。

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.