A novel cannabinoid receptor in cortical nerve terminals

描述（由申请人提供）：大麻是最广泛使用的精神药物之一，它与许多严重的不良反应有关，包括依赖性、精神障碍和心肺疾病。详细了解这种药物的作用机制对于了解其许多作用至关重要，并可能大大有助于设计药物以促进大麻依赖和戒断治疗。所有大麻素受体的鉴定是这个问题的核心。除了两种典型的大麻素受体外，最近还鉴定了另外三种受体。基于其在大脑中的分布和功能，也有人认为细胞外钙敏感受体（CaSR）将是大麻素的合适靶点。在初步实验中，我们发现大麻素激活CaSR，这是一种G蛋白偶联受体（GPCR），位于大脑中的大多数神经末梢中，并在激活时减少突触传递。这些初步发现，加上大脑中丰富的CaSR，可能会从根本上改变我们对大麻素作用机制的理解。该提案的目的是确定CaSR是否是大麻素作用的重要途径，我们的假设是大脑CaSR直接被大麻素激活。我们非常适合执行这个项目，因为我们在神经末梢和表达系统中的CaSR功能方面的专业知识。CaSR对大麻素的敏感性和CaSR在大脑中的流行将开辟大麻素作用的新视角，大大改变该领域的思维。成功完成这些特定目标将表征CaSR对大麻素的反应，揭示CaSR更广泛的影响范围。这项工作将定义必要的工具来剖析CaSR和CB1对大脑中突触传递的大麻素调制的相对贡献。未来的建议将结合联合收割机药理学和遗传学的方法，以确定大麻素通过CB1和CaSR在中央突触的影响。我们的理由是，一种新的和普遍的大麻素受体的鉴定和表征将有助于我们了解常用药物大麻的行为作用。此外，区分大麻素的各种作用可能会转化为识别一类新的药物，有助于治疗大麻成瘾和戒断。 公共卫生相关性：大麻是一种常用药物，与药物依赖和严重的精神、心血管和肺部疾病有关。需要新的治疗方法来帮助人们停止使用大麻，但这需要更好地了解大麻是如何工作的。我们在大脑中发现了一条新的通路，它被大麻类药物激活。通过研究这一新途径，我们将更多地了解大麻的作用机制，从而提高设计新治疗方法以帮助阻止大麻使用的机会。

DESCRIPTION (provided by applicant): Cannabis is one of the most widely used psychotropic drugs and it has been linked with numerous serious adverse effects including dependence, psychiatric disorders, and cardio-respiratory disease. Detailed knowledge about the mechanisms by which this drug acts is crucial to understand its many effects, and may greatly assist the design of drugs to facilitate treatment of cannabis dependence and withdrawal. Identification of all the cannabinoid receptors is central to this problem. In addition to the two well-characterized classical cannabinoid receptors three other receptors have recently been identified. Based on its distribution and function in the brain it has also been suggested that the extracellular Ca-sensing receptor (CaSR) would be a suitable target for cannabinoids. In preliminary experiments we found that cannabinoids activate CaSR, a G-protein coupled receptor (GPCR), that is localized in the majority of nerve terminals in the brain, and decreases synaptic transmission when activated. These preliminary findings, coupled with the abundance of CaSR in the brain, may fundamentally change our understanding of the mechanism of action of cannabinoids. The objective of this proposal is to determine if CaSR is an important pathway in the action of cannabinoids and our hypothesis is that brain CaSR is activated directly by cannabinoids. We are ideally suited to perform this project because of our expertise in CaSR function in nerve terminals and expression systems. The sensitivity of CaSR to cannabinoids and the prevalence of CaSR in the brain will open up a new view of cannabinoid action, substantially changing thinking in the field. Successful completion of these specific aims will characterize the response of CaSR to cannabinoids, shedding light on the broader range of influence of CaSR. This work will define the tools necessary to dissect the relative contributions of CaSR and CB1 to cannabinoid modulation of synaptic transmission in the brain. Future proposals would combine pharmacological and genetic approaches to ascertain the impact of cannabinoids via CB1 and CaSR at central synapses. Our rationale is that the identification and characterization of a novel and prevalent cannabinoid receptor will facilitate our understanding of the behavioral actions of the commonly used drug cannabis. Moreover, distinguishing the various actions of cannabinoids may translate into the identification of a novel class of drugs that facilitate treatment of cannabis addiction and withdrawal. PUBLIC HEALTH RELEVANCE: Cannabis is a commonly used drug that is associated with drug dependence and serious psychiatric, cardiovascular and pulmonary diseases. New treatments are needed to help people stop using cannabis but this requires improved understanding of how cannabis works. We have discovered a new pathway in the brain that is activated by cannabis-like drugs. By studying this new pathway we will discover more about how cannabis works and so improve the chances of designing new treatments to help stop cannabis use.