NEURONAL CANNABINOID RECEPTOR: FUNCTION AND REGULATION

神经元大麻素受体：功能和调节

• 批准号: 7013234
• 负责人: Kenneth Mackie
• 金额: $ 25.91万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7013234
• 关键词: biological signal transduction; calcium channel; cannabinoid receptor; dopamine; drug tolerance; electrophysiology; enzyme substrate; hippocampus; immunocytochemistry; laboratory mouse; neuropharmacology; neuroregulation; neurotransmitter antagonist; neurotransmitter transport; phosphorylation; potassium channel; protein structure function; receptor expression; receptor sensitivity; synaptic vesicles; tissue /cell culture; voltage /patch clamp; voltage gated channel; western blottings

DESCRIPTION (provided by applicant): Endogenous cannabinoids (endocannabinoids) and the CB1 cannabinoid receptor form a signaling system that plays a key role in several forms of short and long term neuronal plasticity. In addition, CB1 receptors are the primary target of cannabis, the most commonly used illicit drug in the US. Despite an increasing awareness of the importance of the cannabinoid signaling system in normal and pathological CNS function, the potential therapies targeting this system, and the social impact of cannabis use, our knowledge of how CB1 receptors and endocannabinoid production is regulated is quite modest. Understanding the control of the endocannabinoid system is vital to the rational assessment of therapies affecting this system, as well as to appreciating the impact of chronic activation of this system (as might happen therapeutically or by excessive cannabis use). In the proposed work we will address three specific aims: Is desensitization of cannabinoid inhibition of neurotransmission due to phosphorylation of the CB1 receptor at residues $426 and $430? Does regulated association of CB1 cannabinoid and D2 dopamine receptors underlie some of the interactions between dopamine and cannabinoid signaling? Which endocannabinoids are secreted by cultured neurons and from where are they released? By accomplishing these specific aims we will have a firm understanding of the molecular events associated with desensitization of CB1 receptor signaling, insight into the interactions between the cannabinoid and dopamine signaling pathways, knowledge of the endocannabinoids released by neurons and the domains of the neuron important in endocannabinoid release.

描述（由申请人提供）：内源性大麻素（endocannabinoids）和CB1大麻素受体形成信号系统，在多种形式的短期和长期神经元可塑性中发挥关键作用。此外，CB1 受体是大麻（美国最常用的非法药物）的主要目标。尽管人们越来越认识到大麻素信号系统在正常和病理性中枢神经系统功能中的重要性、针对该系统的潜在疗法以及大麻使用的社会影响，但我们对 CB1 受体和内源性大麻素产生如何调节的了解相当有限。了解内源性大麻素系统的控制对于合理评估影响该系统的疗法以及理解该系统慢性激活的影响（如治疗或过度使用大麻可能发生的情况）至关重要。在拟议的工作中，我们将解决三个具体目标：大麻素脱敏是否会由于 CB1 受体在残基 426 和 430 处的磷酸化而抑制神经传递？ CB1 大麻素和 D2 多巴胺受体的调节关联是否是多巴胺和大麻素信号传导之间某些相互作用的基础？哪些内源性大麻素是由培养的神经元分泌的，它们从哪里释放？通过实现这些具体目标，我们将深入了解与 CB1 受体信号传导脱敏相关的分子事件，深入了解大麻素和多巴胺信号传导途径之间的相互作用，了解神经元释放的内源性大麻素以及神经元在内源性大麻素释放。