Role of the scaffolding protein SLC9A3R1 in the vomeronasal organ - from protein interactions to the physiology of pheromone detection

在大多数哺乳动物中，犁鼻系统检测到各种（半）化学物质，这些化学物质介导嗅觉驱动的社会和性行为。鼻口化学感觉依赖于G蛋白偶联受体（V1R, V2R, FPR-rs），这些受体在非常低的刺激浓度下起作用，因此表明了一个高度敏感和有效的信号通路。因此，我们假设a) v形鼻信号级联蛋白在微结构域中组织以确保最佳的信号转导，b)这些结构域的组装涉及支架蛋白。在目前的提议中，我们的目的是鉴定和研究含有PDZ结构域的蛋白作为犁鼻神经元信号转导的假定分子组织者。因此，本研究的一个主要目标是分析支架蛋白在形成超敏感和高选择性信息素反应中的功能作用。SLC9A3R1是一种含有两个PDZ结构域和一个羧基末端ezrin结合结构域的蛋白质，是我们的研究重点。我们将确定基于SLC9A3R1的犁鼻支架的分子组成，研究SLC9A3R1、相关受体蛋白和下游信号伙伴的高分辨率分布，并采用一系列生理学方法阐明蛋白质-蛋白质相互作用在犁鼻信号传导中的功能。

In most mammals, the vomeronasal system detects of a variety of (semio)chemicals that mediate olfactory-driven social and sexual behaviors. Vomeronasal chemosensation depends on G protein-coupled receptors (V1R, V2R, FPR-rs) that operate at remarkably low stimulus concentrations, thus, indicating a highly sensitive and efficient signaling pathway. We therefore hypothesize a) that vomeronasal signaling cascade proteins are organized in microdomains to ensure optimal signal transduction, and b) that the assembly of these domains involves scaffolding proteins. In the present proposal, we aim to identify and investigate PDZ domain-containing proteins as putative molecular organizers of signal transduction in vomeronasal neurons. Accordingly, a major goal of this research is to analyze the functional role of scaffolding proteins in shaping ultrasensitive and highly selective pheromone responses. SLC9A3R1, a protein that contains two PDZ domains and a carboxy-terminal ezrin-binding domain, is the focus of our interest. We will identify the molecular composition of vomeronasal SLC9A3R1-based scaffolds, study distribution of SLC9A3R1, associated receptor proteins and downstream signaling partners at high resolution, and employ an array of physiological approaches to elucidate the function of protein - protein interactions in vomeronasal signaling.