SAP97 Isoforms in Trafficking Synaptic GluR1

描述（由申请人提供）： 中枢神经系统突触的组装和可塑性与其单个成分的动态募集和周转密切相关。特别重要的是突触-α-氨基-5-羟基-3-甲基-4-异恶唑丙酸酯（AMPA）受体的插入和去除。这已被证明对于在兴奋性突触处建立复发性信号传导以及设定突触的动态范围至关重要，如在建立某些形式的长期抑制（LTD）或增强（LTP）期间发生的。已知与AMPA受体的胞质结构域相互作用的衔接蛋白如SAP 97、Grip和Pick 1被认为对于受体运输以及突触定位和功能是重要的。其中SAP 97是对含有GluR 1亚基的AMPA受体的运输和突触定位最重要的蛋白之一。特别地，已经发现这种多结构域支架蛋白与内质网（ER）、高尔基体和突触中的GluR 1亚基相关。令人兴奋的是，在我们最近的初步数据中，我们已经发现，突触异构体的SAP 97功能影响的AMPA受体含有GluR 1亚基的突触募集。因此，我们假设SAP 97亚型在AMPA受体的突触GluR 1亚基的运输和动态插入中发挥直接和不可或缺的作用。在本申请中，我们建议测试这些和其他假设的作用，具体的SAP 97亚型发挥在运输的GluR 1受体，以及组装的多组分蛋白复合物周围GluRI。这些问题对于理解突触AMPA受体动态特性的细胞和分子机制至关重要，并且与学习和记忆问题以及滥用药物如何显著影响这些受体的行为和神经回路的活动有关。

DESCRIPTION (provided by applicant): The assembly and plasticity of CNS synapses is intimately linked to the dynamic recruitment and turnover of its individual components. Of particular importance is the insertion and removal of synaptic -a-amino-5- hydroxy-3methyl-4-isoxacole propionate (AMPA) receptors. This has been shown to be critically important for the establishment of recurrent signaling at excitatory synapses as well as in setting the dynamic range of synapses as occurs during the establishment of certain forms of long term depression (LTD) or potentiation (LTP). Adapter proteins such SAP97, Grip and Pick1, known to interact with the cytoplasmic domains of AMPA receptors are thought to be important for receptor trafficking as well as synaptic localization and function. Of these SAP97 is emerging as one of the most important for trafficking and synaptic localization of AMPA receptors containing GluR1 subunits. In particular, this multidomain scaffold protein has been found to associate with GluR1 subunits in the endoplasmic reticulum (ER), Golgi and synapses. Excitingly, in our recent preliminary data, we have found that synaptic isoforms of SAP97 functionally affect the synaptic recruitment of AMPA receptors contain GluR1 subunits. As such, we hypothesize that SAP97 isoforms play a direct and integral role in the trafficking and dynamic insertion of synaptic GluR1 subunits of the AMPA receptor. In this application, we propose to test these and other hypotheses regarding the role that specific SAP97 isoforms play in the trafficking of GluR1 receptors as well as the assembly of multi-component protein complexes around GluRI. These issues are critical for understanding the cellular and molecular mechanisms underlying the dynamic properties of synaptic AMPA receptors and are relevant to issues of learning and memory and how drugs of abuse dramatically influence the behavior of these receptors and the activity of neural circuits.