STRUCTURE/FUNCTION OF CB2 CANNABINOID RECEPTOR

描述：（申请人摘要） 这项研究计划的总体目的是确定 CB 2大麻素受体的功能基础。 之一 大麻素作为治疗剂的主要问题是它们的严重 精神副作用 最近克隆的CB 2，一种亚型， 大麻素受体，给我们带来了新的希望， 大麻素 CB 2主要分布在外周组织中， 而CB 1 I主要分布于中枢神经系统。 CB 2有 只有44%的氨基酸与CB 1相同。 最近几个 已经发现了CB 2-选择性大麻素配体; CB 2的转导途径正在鉴定中; CB 2在大鼠肥大细胞系RBL-2 H3细胞中的特性已经显示， 与克隆的人CB 2不同。 关于这一点的假设 建议包括：1. 配体结合和信号转导 CB 2的特性由其独特的结构特征决定。 2. RBL-2 H3细胞大麻素受体和人CB 2之间的差异可能是由于RBL-2 H3细胞大麻素受体与人CB 2之间的差异而引起的。 可以用大鼠和人类CB 2之间的结构差异来解释， 或可能存在于RBL-2 H3细胞中的新受体亚型。 的 以下具体目标将试图检验这些假设： 具体目的1：确定CB 2的氨基酸， 重要 用于配体结合。 具体目标2：确定CB 2的氨基酸， 重要 用于受体激活。 具体目标3：表征在一个或多个神经元中的大麻素受体亚型。 大鼠 肥大细胞系（RBL-2 H3）。 结合分子克隆， 诱变、异源表达和药理学测定将被 用于测试本提案的假设。 分子建模 研究将合作进行。 这些研究将帮助我们 更详细地了解配体结合和激活 大麻素受体亚型，特别是CB 2，这是一个非常重要的 大麻免疫调节作用的重要受体， 大麻素 最终，这可能会促进小说的发展 具有改善的治疗性质和最小化的大麻素模拟物 精神副作用

DESCRIPTION: (Applicant's Abstract) The overall purpose of this research proposal is to identify the molecular basis underlying the functions of the CB2 cannabinoid receptor. One of the major problems for cannabinoids as therapeutic agents is their severe psychoactive side-effect. The recent cloning of CB2, a subtype of cannabinoid receptors, brought us new hope for a better medical use of cannabinoids. CB2 is distributed primarily in the peripheral tissues, whereas CB1 I distributed primary in the central nervous system. CB2 has only 44 percent amino acid identity with CB1. Recently several CB2-selective cannabinoid ligands have been discovered; the signal transduction pathway for CB2 is being identified; and the pharmacological properties of CB2 in a rat mast cell line, RBL-2H3 cells, have been shown to be different from those of the cloned human CB2. The hypotheses of this proposal include: 1. The ligand binding and signal transduction characteristics of CB2 are determined by its unique structural features. 2. The differences between RBL-2H3 cell cannabinoid receptors and human CB2 may be explained by either the structural differences between rat and human CB2, or the novel receptor subtypes that may exist in RBL-2H3 cells. The following specific aims will attempt to test these hypotheses: Specific Aim 1: To determine the amino acids of CB2 that are important for ligand binding. Specific Aim 2: To determine the amino acids of CB2 that are important for receptor activation. Specific Aim 3: To characterize cannabinoid receptor subtypes in a rat mast cell line (RBL-2H3). A combination of molecular cloning, mutagenesis, heterologous expression, and pharmacological assays will be utilized to test the hypotheses of this proposal. Molecular modeling studies will be performed collaboratively. These studies should help us to understand in more molecular detail the ligand binding and activation of cannabinoid receptor subtypes, particularly about CB2, which is a very important receptor for the immune-modulatory effects of marijuana and cannabinoids. Ultimately, this may facilitate the development of novel cannabinoid mimetics with improved therapeutic properties and minimized psychoactive side effects.