Determinants of the Cannabinoid Receptor Life Cycle

大麻素受体生命周期的决定因素

基本信息

  • 批准号:
    8104214
  • 负责人:
  • 金额:
    $ 28.8万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-09-25 至 2015-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The human cannabinoid receptor one (CB1) binds ?9-tetrahydrocannabinol, the psychoactive component of Cannabis sativa L., and other cannabimimetic compounds. It is a G-protein coupled receptor (GPCR) that is associated with the central nervous system and exerts its effects primarily via coupling to Gi/Go proteins. The pharmacological effects of CB1 agonists include analgesia, inhibition of nausea, appetite stimulation, antiemetic activity and bronchial dilation while inverse agonists attenuate excessive eating disorders. Any therapeutic strategy targeting CB1 will require that we have a firm understanding of the structural features of the receptor that impact key points in its life cycle: ER integration and cell surface expression, receptor activation, and desensitization and internalization. In Aim 1, we will examine the basis for the weak ER translocation of the CB1 amino terminus (N-tail). The structure of the N-terminus will be determined and accessory proteins and their recognition motifs in the N- and C-terminus will be identified. The role of these motifs in cellular localization including sematodendritic and axonal membrane surface localization in neurons will be examined. In Aim 2, we will build on our identification of structural elements of the receptor critical for distinguishing agonist and inverse agonist interactions and fully map the key contact points in the TM domain and the extracellular region of CB1 that are involved. We will define residues critical for poising the ligand- independent equilibrium of CB1 atypically toward activation and those responsible for the interconversion of this intermediate receptor state to the resting and activated forms of the receptor. In Aim 3, we will take advantage of novel receptor mutants that model different structural states of the receptor to examine linkages between receptor activation, desensitization, and cellular localization. Mutants that model the inactive and active forms of CB1 will provide tools for analyzing the consequences of prolonged treatment with inverse agonists and agonists. We will utilize our expertise in developing structural analyses and binding assays with purified components to examine the molecular basis of these processes with emphasis on the carboxyl terminus (C-tail) of the receptor. In the course of this work we will identify determinants that enhance the cell surface expression of CB1 and strategies for the large-scale preparation of domains of the receptor, and their structural analysis, which could be applied to structural studies of other GPCRs and membrane proteins in general. RELEVANCE: The cannabinoid receptor one (CB1) is a G-protein coupled receptor that is associated with the central nervous system. Research activities that have focused on the role of CB1 in signal transduction have underscored its enormous potential as a target for therapeutic agents. The goal of this project is to understand the structural features that influence key stages in the life cycle of CB1 including cell surface expression, receptor activation, and internalization and ultimately impact its cell surface exposure so that it will be accessible for therapeutic strategies.
描述(由申请人提供):人类大麻素受体ONE(CB1)结合了9-四氢大麻酚,大麻sativa L.的精神活性成分和其他大麻型化合物。它是一种与中枢神经系统相关的G蛋白偶联受体(GPCR),主要通过与GI/GO蛋白耦合发挥作用。 CB1激动剂的药理作用包括镇痛,抑制恶心,食欲刺激,抗体活性和支气管扩张,而反激动剂会减弱过度的饮食失调。任何针对CB1的治疗策略都将要求我们对受体的结构特征有牢固的了解,从而影响其生命周期中的关键点:ER整合和细胞表面表达,受体激活以及脱敏和内在化。在AIM 1中,我们将研究CB1 Amino末端(N-Tail)的ER易位易位的基础。将确定N末端的结构,并确定辅助蛋白及其识别基序。这些基序在细胞定位中的作用将研究在神经元中的半末端和轴突膜表面定位。在AIM 2中,我们将建立在对区分激动剂和反向激动剂相互作用至关重要的受体结构元素上的识别,并充分绘制涉及的TM域和CB1细胞外区域中的关键接触点。我们将定义残基,对于在非典型上朝着CB1的配体独立平衡以及负责该中间受体状态与受体的静止和激活形式的互转换的残基至关重要。在AIM 3中,我们将利用新型受体突变体,该突变体对受体的不同结构状态进行模拟,以检查受体激活,脱敏和细胞定位之间的联系。对CB1的不活跃和主动形式进行建模的突变体将提供工具,以分析长期治疗的后果,反向激动剂和激动剂。我们将利用我们的专业知识来开发具有纯化成分的结构分析和结合测定,以检查这些过程的分子基础,重点是受体的羧基末端(C-Tail)。在这项工作的过程中,我们将确定确定的决定因素,以增强CB1的细胞表面表达以及用于大规模制备受体结构域的策略及其结构分析,这些分析可以应用于其他GPCR和膜蛋白的结构研究。相关性:大麻素受体ONE(CB1)是与中枢神经系统相关的G蛋白偶联受体。关注CB1在信号转导中作用的研究活动突显了其作为治疗剂的范围的巨大潜力。该项目的目的是了解影响CB1生命周期中关键阶段的结构特征,包括细胞表面表达,受体激活和内在化,并最终影响其细胞表面暴露,以便可以使用治疗策略。

项目成果

期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Optimization of chemical functionalities of indole-2-carboxamides to improve allosteric parameters for the cannabinoid receptor 1 (CB1).
  • DOI:
    10.1021/jm5000112
  • 发表时间:
    2014-04-10
  • 期刊:
  • 影响因子:
    7.3
  • 作者:
    Khurana L;Ali HI;Olszewska T;Ahn KH;Damaraju A;Kendall DA;Lu D
  • 通讯作者:
    Lu D
Structure-activity relationship study of indole-2-carboxamides identifies a potent allosteric modulator for the cannabinoid receptor 1 (CB1).
  • DOI:
    10.1021/jm4009828
  • 发表时间:
    2013-10-24
  • 期刊:
  • 影响因子:
    7.3
  • 作者:
    Mahmoud MM;Ali HI;Ahn KH;Damaraju A;Samala S;Pulipati VK;Kolluru S;Kendall DA;Lu D
  • 通讯作者:
    Lu D
Profiling two indole-2-carboxamides for allosteric modulation of the CB1 receptor.
  • DOI:
    10.1111/jnc.12115
  • 发表时间:
    2013-03
  • 期刊:
  • 影响因子:
    4.7
  • 作者:
    Ahn KH;Mahmoud MM;Samala S;Lu D;Kendall DA
  • 通讯作者:
    Kendall DA
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

DEBRA A KENDALL其他文献

DEBRA A KENDALL的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('DEBRA A KENDALL', 18)}}的其他基金

CB1 Allosteric Modulators: Molecular, Cellular and In Vivo Pharmacology
CB1 变构调节剂:分子、细胞和体内药理学
  • 批准号:
    9259973
  • 财政年份:
    2016
  • 资助金额:
    $ 28.8万
  • 项目类别:
Beta-Arrestin Signaling from the Cannabinoid 2 and mu Opioid Receptors
来自大麻素 2 和 mu 阿片受体的 Beta-Arrestin 信号传导
  • 批准号:
    9176213
  • 财政年份:
    2016
  • 资助金额:
    $ 28.8万
  • 项目类别:
CB1 Allosteric Modulators: Molecular, Cellular and In Vivo Pharmacology
CB1 变构调节剂:分子、细胞和体内药理学
  • 批准号:
    9056090
  • 财政年份:
    2016
  • 资助金额:
    $ 28.8万
  • 项目类别:
Redesign of Structural Regions of Alkaline Phosphatase
碱性磷酸酶结构区域的重新设计
  • 批准号:
    7935894
  • 财政年份:
    2009
  • 资助金额:
    $ 28.8万
  • 项目类别:
Determinants of the Cannabinoid Receptor Life Cycle
大麻素受体生命周期的决定因素
  • 批准号:
    7371515
  • 财政年份:
    2007
  • 资助金额:
    $ 28.8万
  • 项目类别:
Determinants of the Cannabinoid Receptor Life Cycle
大麻素受体生命周期的决定因素
  • 批准号:
    7666247
  • 财政年份:
    2007
  • 资助金额:
    $ 28.8万
  • 项目类别:
Determinants of the Cannabinoid Receptor Life Cycle
大麻素受体生命周期的决定因素
  • 批准号:
    7500661
  • 财政年份:
    2007
  • 资助金额:
    $ 28.8万
  • 项目类别:
Determinants of the Cannabinoid Receptor Life Cycle
大麻素受体生命周期的决定因素
  • 批准号:
    7870475
  • 财政年份:
    2007
  • 资助金额:
    $ 28.8万
  • 项目类别:
REDESIGN OF STRUCTURAL REGIONS OF ALKALINE PHOSPHATASE
碱性磷酸酶结构区域的重新设计
  • 批准号:
    2761797
  • 财政年份:
    1989
  • 资助金额:
    $ 28.8万
  • 项目类别:
REDESIGN OF STRUCTURAL REGIONS OF ALKALINE PHOSPHATASE
碱性磷酸酶结构区域的重新设计
  • 批准号:
    2178854
  • 财政年份:
    1989
  • 资助金额:
    $ 28.8万
  • 项目类别:

相似海外基金

Identification of genes and genetic networks contributing to opioid use disorder traits in the Hybrid Rat Diversity Panel
杂交大鼠多样性面板中导致阿片类药物使用障碍特征的基因和遗传网络的鉴定
  • 批准号:
    10219230
  • 财政年份:
    2020
  • 资助金额:
    $ 28.8万
  • 项目类别:
Identification of genes and genetic networks contributing to opioid use disorder traits in the Hybrid Rat Diversity Panel
杂交大鼠多样性面板中导致阿片类药物使用障碍特征的基因和遗传网络的鉴定
  • 批准号:
    10056472
  • 财政年份:
    2020
  • 资助金额:
    $ 28.8万
  • 项目类别:
Identification of genes and genetic networks contributing to opioid use disorder traits in the Hybrid Rat Diversity Panel
杂交大鼠多样性面板中导致阿片类药物使用障碍特征的基因和遗传网络的鉴定
  • 批准号:
    10403624
  • 财政年份:
    2020
  • 资助金额:
    $ 28.8万
  • 项目类别:
Effects of Long-Term Morphine Treatment on Opioid Receptor Signaling and Inflammation in the Chronic Post-TBI Period
长期吗啡治疗对慢性 TBI 后阿片受体信号传导和炎症的影响
  • 批准号:
    10454092
  • 财政年份:
    2019
  • 资助金额:
    $ 28.8万
  • 项目类别:
Neuropathic Pain-induced Depression: the Role of mPFC Endocannabinoids
神经性疼痛诱发的抑郁症:mPFC 内源性大麻素的作用
  • 批准号:
    9797432
  • 财政年份:
    2019
  • 资助金额:
    $ 28.8万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了