Central calcium and cannabinoid signaling

描述（由申请人提供）：大麻是使用最广泛的非法药物，它与许多严重的不良反应有关。大麻也被提议作为几种神经系统疾病的有效治疗方法，包括慢性疼痛，艾滋病相关的肌肉萎缩和运动障碍。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上述疾病的治疗。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。基于细胞外钙敏感受体（CaSR）在脑中的分布和功能，已表明它是大麻素的潜在靶点。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，CaSR的激活调节突触传递。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，以及大脑CaSR是否直接被大麻素激活。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。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，并大大改变该领域的思维。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几种神经系统疾病。

DESCRIPTION (provided by applicant): Cannabis is the most widely used illegal drug and it has been linked with numerous serious adverse effects. Cannabis has also been proposed as useful therapy for several neurological conditions including chronic pain, AIDS-related muscle wasting, and movement disorders. Detailed knowledge about the mechanisms by which this drug acts is crucial to understanding its many effects, and may greatly assist in the design of drugs to facilitate treatment of cannabis dependence and the above diseases. In addition to the two well-characterized classical cannabinoid receptors three other receptors have recently been identified. Based on the distribution and function in the brain of the extracellular Ca-sensing receptor (CaSR) it has been suggested that it a potential target for cannabinoids. In preliminary experiments we found that cannabinoids activate CaSR, a G-protein coupled receptor (GPCR), localized in the majority of nerve terminals in the brain, and activation of CaSR modulates synaptic transmission. These preliminary findings, coupled with the abundance of CaSR in the brain, may fundamentally change our understanding of the mechanisms of cannabinoid action. The objective of this proposal is to determine if CaSR is an important pathway in the action of cannabinoids and whether 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. Successful completion of these specific aims will characterize the response of CaSR to cannabinoids, shedding light on the broader range of influence of CaSR and substantially change the thinking in this field. 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 several neurological diseases.