Ligand selectivity of vomeronasal receptors

描述（由申请人提供）：犁鼻器中表达的三个受体家族-V1 Rs、V2 Rs和FPRs-的配体选择性在很大程度上是未知的。为了加深我们对犁鼻受体及其配体之间相互作用的理解，我们建议建立系统来识别V2 Rs和FPRs的活性配体。此外，我们建议，以确定哪些领域的受体蛋白决定配体的选择性。为了检验特异性V2 R或FPR犁鼻受体被特异性配体组激活的假设，提出了三个特异性目的：特异性目的1。表征V2 Rs的配体选择性。 我们将建立V2 Rs的异源表达系统。我们将使用这个系统来识别V2 R的活性配体，并研究V2 R家族成员的配体选择性的结构基础。 具体目标2：表征VNO-FPR的配体选择性。 我们将建立VNO-FPRs的异源表达系统。我们将使用该系统来鉴定VNO-FPRs的活性配体。 具体目标3：使用VNO感觉神经元表征VNO受体的配体选择性。 我们将建立一个系统，用于测量分离的犁鼻神经元的反应，然后测量在相同的细胞中的mRNA表达的钙成像。我们将使用这种方法来识别由给定配体激活的细胞中表达的受体。 提出的实验进一步我们的长期目标，这是了解犁鼻受体的配体识别的机制基础。 这些研究的健康相关性在于，更好地理解犁鼻受体的配体结合属性将提供对G蛋白偶联受体（一类经常被药物靶向的受体）的配体识别的一般特征的见解。这项工作将提高我们对G蛋白偶联犁鼻受体如何识别和区分特定配体的理解。这些基础知识将转化为对G蛋白偶联受体的更好理解，G蛋白偶联受体是心脏病，精神病和癌症疾病状态的主要药物靶点。对配体和受体之间相互作用的理解提供了开发各种健康相关产品所需的关键信息。

DESCRIPTION (provided by applicant): The ligand selectivity of the three families of receptors expressed in the vomeronasal organ-V1Rs, V2Rs and FPRs-is largely unknown. To deepen our understanding of the interactions between the vomeronasal receptors and their ligands, we propose to establish systems to identify active ligands for the V2Rs and the FPRs. In addition, we propose to identify which domains of the receptor proteins determine ligand selectivity. To test the hypothesis that specific V2R or FPR vomeronasal receptors are activated by specific set of ligands, three Specific Aims are proposed: Specific Aim 1. Characterize the ligand selectivity of V2Rs. We will establish a heterologous expression system for the V2Rs. We will use this system to identify active ligands of the V2Rs and examine the structural basis of ligand selectivity by V2R family members. Specific Aim 2: Characterize the ligand selectivity of VNO-FPRs. We will establish a heterologous expression system for the VNO-FPRs. We will use this system to identify the active ligands of VNO-FPRs. Specific Aim 3: Characterize the ligand selectivity of VNO receptors using VNO sensory neurons. We will establish a system for measuring the response of dissociated vomeronasal neurons using calcium imaging and then measuring the mRNA expression in the same cells. We will use this method to identify the receptors expressed in the cells activated by a given ligand. The proposed experiments further our long term goal, which is to understand the mechanistic basis for ligand recognition by the vomeronasal receptors. The health relatedness of these studies is that a better understanding of the ligand binding attributes of vomeronasal receptors will offer insights into the general features of ligand recognition by G-protein coupled receptors, a class of receptor that is frequently targeted by drugs. This work will improve our understanding of how G protein-coupled vomeronasal receptors recognize and discriminate specific ligands. This basic knowledge will translate to greater understanding of G protein-coupled receptors, which are major pharmaceutical targets for cardiac, psychiatric, and cancer disease states. An understanding of the interactions between the ligand and receptor provides crucial information needed to develop a wide range of health-related products.