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招募和周转密切相关。尤其重要的是突触-α-氨基-5-羟基-3甲基-4-异恶唑丙酸酯(AMPA)受体的插入和移除。这对于兴奋性突触的递归信号的建立以及在某些形式的长期抑制(LTD)或增强(LTP)的建立过程中设置突触的动态范围是至关重要的。SAP97、GRIP和PICK1等适配器蛋白与AMPA受体的胞浆区相互作用，被认为对受体运输以及突触的定位和功能都是重要的。其中，SAP97是对含有GluR1亚单位的AMPA受体运输和突触定位最重要的因子之一。特别是，这种多结构域支架蛋白被发现与内质网(ER)、高尔基体和突触中的GluR1亚基有关。令人兴奋的是，在我们最近的初步数据中，我们发现SAP97的突触异构体在功能上影响含有GluR1亚单位的AMPA受体的突触募集。因此，我们假设SAP97亚型在AMPA受体的突触GluR1亚单位的运输和动态插入中起着直接和完整的作用。在这一应用中，我们建议测试这些假设和其他关于特定SAP97亚型在GluR1受体的运输以及GluRI周围多组分蛋白质复合体组装中所起作用的假设。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，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.