STRUCTURE/FUNCTION OF CB2 CANNABINOID RECEPTOR

CB2 大麻素受体的结构/功能

• 批准号: 6174723
• 负责人: ZHAO-HUI SONG
• 金额: $ 9.92万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6174723
• 关键词: animal genetic material tag; cannabinoid receptor; cannabinoids; immunopharmacology; laboratory rat; mast cell; molecular cloning; protein structure function; receptor binding; receptor expression; site directed mutagenesis

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.

描述：（申请人摘要） 本研究计划的总体目的是确定分子 CB2 大麻素受体功能的基础。 中的一个 大麻素作为治疗剂的主要问题是其严重的 精神活性副作用。 最近克隆的 CB2（CB2 的一个亚型） 大麻素受体，给我们带来了更好的医疗用途的新希望 大麻素。 CB2主要分布于外周组织， 而CB1 I主要分布在中枢神经系统。 CB2有 与 CB1 仅有 44% 的氨基酸同一性。 最近几 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；以及药理作用 CB2 在大鼠肥大细胞系 RBL-2H3 细胞中的特性已被证明 与克隆人CB2的不同。 本研究的假设 提案内容包括： 1. 配体结合与信号转导 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之间的差异可能 可以通过大鼠和人类 CB2 之间的结构差异来解释， 或RBL-2H3细胞中可能存在的新受体亚型。 这 以下具体目标将尝试检验这些假设： 具体目标 1：确定 CB2 的氨基酸 重要的 用于配体结合。 具体目标 2：确定 CB2 的氨基酸 重要的 用于受体激活。 具体目标 3：表征大麻素受体亚型 鼠 肥大细胞系（RBL-2H3）。 结合分子克隆， 诱变、异源表达和药理学测定将 用于检验该提案的假设。 分子建模 研究将合作进行。 这些研究应该可以帮助我们 更详细地了解配体结合和激活 大麻素受体亚型，特别是 CB2，这是一种非常 大麻免疫调节作用的重要受体 大麻素。 最终，这可能会促进新颖的开发 大麻素模拟物具有改善的治疗特性和最小化 精神活性副作用。