Exploring RGS14 signaling functions in the CA2 hippocampus

描述（由申请人提供）：我们最近发现RGS 14是CA 2海马神经元中突触可塑性/LTP和基于海马的学习和记忆的新型抑制剂。这些研究是第一个暗示这个基因/蛋白质（RGS 14）和这个海马区（CA 2）在突触可塑性与学习和记忆。关于大脑神秘的CA 2区域、那里的常驻基因或RGS 14调节那里的LTP的潜在分子机制，人们知之甚少。我们已经发现RGS 14是一种多功能支架蛋白，其整合G蛋白和H-Ras/Raf/ERK信号以抑制某些形式的生长因子指导的MAP激酶信号。RGS 14含有结合活性Gi/o 1-GTP（RGS结构域）、非活性Gi 11/2-GDP（GPR/GL结构域）和活性H-Ras/Rap 2和Raf（串联Ras结合结构域，或RBD）的特异性结构域。已经在CA 2神经元中鉴定了几种其他信号传导蛋白和途径，其调节那里的LTP，并且还与RGS 14结合伴侣（Gi/o-连接的A1腺苷受体、EGF和FGF Tyr-激酶受体，其与H-Ras/Raf/MAP激酶信号传导连接）连接。我的工作假设是RGS 14整合了对调节海马CA 2神经元突触可塑性至关重要的关键信号通路。这些研究的目标将是开发实验工具，并确定（未来的研究）RGS 14在CA 2神经元中与调节突触可塑性的分子信号通路。具体目标是：目标1：开发新型慢病毒递送系统，使我们能够挽救CA 2神经元中丢失的RGS 14功能（抑制LTP），并测试CA 1神经元中RGS 14的表达是否抑制那里的突触可塑性。 目标二：开发编码RGS 14靶向功能丧失突变的新型慢病毒，这将决定不同RGS 14信号传导伙伴/途径在CA 2突触可塑性/LTP调节中的作用。 目的3：确定RGS 14如何与已知的调节CA 2神经元LTP的信号机制相互作用。 影响：这些研究将产生新的实验工具，以确定RGS 14的哪些已识别信号功能对其在CA 2神经元中的作用最重要（从而有助于指导未来的研究），并确定RGS 14与CA 2神经元中的哪些已知通路相互作用，以调节对关键人类认知功能重要的突触可塑性。

DESCRIPTION (provided by applicant): We recently discovered that RGS14 is a novel suppressor of both synaptic plasticity/LTP in CA2 hippocampal neurons and hippocampal-based learning and memory. These studies are the first to implicate this gene/protein (RGS14) and this hippocampal region (CA2) in synaptic plasticity relating to learning and memory. Very little is known about the enigmatic CA2 region of brain, the resident genes there, or the underlying molecular mechanism(s) by which RGS14 regulates LTP there. We have found that RGS14 is a multifunctional scaffolding protein that integrates G protein and H-Ras/Raf/ERK signaling to inhibit certain forms of growth factor-directed MAP kinase signaling. RGS14 contains specific domains that bind active Gi/o1-GTP (RGS domain), inactive Gi11/2-GDP (GPR/GL domain) and active H-Ras/Rap2 and Raf (tandem Ras binding domains, or RBD). Several other signaling proteins and pathways have been identified in CA2 neurons that modulate LTP there, and that also link to RGS14 binding partners (Gi/o-linked A1 adenosine receptors, EGF and FGF Tyr-kinase receptors linked to H-Ras/Raf/MAP kinase signaling). My working hypothesis is that RGS14 integrates key signaling pathways that are critical for regulating synaptic plasticity in hippocampal CA2 neurons. The goal for these studies will be to develop experimental tools and to identify (for future study) molecular signaling pathways that RGS14 interfaces with in CA2 neurons to modulate synaptic plasticity. The Specific Aims will be to: Aim 1: Develop novel lentiviral delivery systems that will allow us to rescue lost RGS14 function (inhibition of LTP) in CA2 neurons, and to test if expression of RGS14 in CA1 neurons suppresses synaptic plasticity there. Aim 2: Develop novel lentiviruses encoding targeted loss-of-function mutations of RGS14 that will determine the role of the different RGS14 signaling partners/pathways in the regulation of CA2 synaptic plasticity/LTP. Aim 3: Determine how RGS14 interacts with known signaling mechanisms that regulate LTP in CA2 neurons. IMPACT: These studies will generate new experimental tools that will determine which of the identified signal functions of RGS14 are most important for its actions in CA2 neurons, (thereby helping to direct future studies), and establish what known pathways in CA2 neurons RGS14 interacts with to regulate synaptic plasticity important for key human cognitive functions.