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，在多种形式的短期和长期神经元可塑性中起关键作用。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。尽管人们越来越意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是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治疗方法，以及了解该系统慢性激活的影响（可能发生在治疗或过量使用大麻）至关重要。在拟议的工作中，我们将解决三个具体目标：大麻素脱敏是否由于CB1受体在426和430残基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构成了多巴胺和大麻素信号传导之间的一些相互作用？哪些内源性大麻素由培养的神经元分泌，从哪里释放？通过完成这些特定目标，我们将对CB1受体信号脱敏相关的分子事件有一个坚定的理解，深入了解大麻素和多巴胺信号通路之间的相互作用，了解神经元释放的内源性大麻素和内源性大麻素释放中重要的神经元区域。

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.