NEURONAL CANNABINOID RECEPTOR: FUNCTION AND REGULATION

描述(由申请人提供)：内源性大麻素(内源性大麻素)和CB1大麻素受体形成一个信号系统，在几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受体是大麻的主要目标，大麻是美国最常用的非法药物。尽管人们越来越认识到大麻素信号系统在正常和病理中枢神经系统功能中的重要性，针对该系统的潜在治疗方法，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的调控知之甚少。了解内源性大麻素系统的控制，对于合理评估影响这一系统的治疗，以及评价这一系统的慢性激活的影响(如在治疗中或过度使用大麻时可能发生的影响)至关重要。在拟议的工作中，我们将解决三个具体目标：由于CB1受体残基的磷酸化而导致的大麻类神经传递抑制的脱敏是否为426美元和430美元？CB1大麻素和D2多巴胺受体的调节关联是否构成了多巴胺和大麻素信号之间的一些相互作用的基础？培养的神经元分泌哪些内源性大麻素？它们是从哪里释放的？通过实现这些特定的目标，我们将对与CB1受体信号脱敏相关的分子事件有更深入的了解，对大麻素和多巴胺信号通路之间的相互作用有更深入的了解，对神经元释放的内源性大麻素和对内源性大麻素释放起重要作用的神经元的结构域有更多的了解。

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.