STRUCTURE/FUNCTION OF CB2 CANNABINOID RECEPTOR

描述：(申请人摘要) 这项研究提案的总体目的是识别分子 CB2大麻素受体功能的基础。其中一个 大麻素类药物作为治疗剂的主要问题是它们严重的 精神活性副作用。新近克隆的Cb2亚型 大麻素受体，为我们带来了更好的医疗用途的新希望 大麻素。CB2主要分布在周围组织中， 而CB1I主要分布于中枢神经系统。CB2有 与CB1的氨基酸同源性仅为44%。最近几次 CB2选择性大麻素配体已被发现；信号 CB2的转导途径正在确定；药理学上 CB2在大鼠肥大细胞系RBL-2H3细胞中的特性已被证明 与克隆的人CB2基因不同。这其中的假设 建议包括：1.配体结合和信号转导 CB2的特性是由其独特的结构特征决定的。2. RBL-2H3细胞大麻素受体与人CB2的差异可能 可以用老鼠和人类CB2之间的结构差异来解释， 或RBL-2H3细胞中可能存在的新的受体亚型。这个 以下具体目标将尝试检验这些假设： 具体目标1：确定CB2中 重要信息 用于配基结合。 具体目标2：确定CB2的氨基酸是 重要信息 用来激活受体。 具体目标3：确定大麻素受体亚型 大鼠 肥大细胞系(RBL-2H3)。分子克隆的结合， 突变、异源表达和药理检测将是 用来检验这一提议的假设。分子建模 研究将以合作方式进行。这些研究应该有助于我们 更详细地了解配体的结合和激活 大麻素受体亚型，特别是关于CB2，这是一种非常 大麻免疫调节作用的重要受体和 大麻素。最终，这可能会促进小说的发展 具有更好的治疗特性和最小化的大麻素模拟物 精神活性副作用。

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.