Central calcium and cannabinoid signaling

描述(申请人提供)：大麻是最广泛使用的非法药物，它与许多严重的不良反应有关。大麻也被认为是治疗几种神经系统疾病的有效疗法，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，并可能极大地有助于设计药物以促进大麻依赖和上述疾病的治疗。除了两个特性良好的经典大麻素受体外，最近还发现了另外三个受体。根据细胞外钙敏感受体(CaSR)在脑内的分布和功能，它被认为是大麻类药物的潜在靶点。在初步实验中，我们发现大麻素激活了定位于大脑大多数神经末梢的G蛋白偶联受体CaSR，并且CaSR的激活调节了突触传递。这些初步发现，再加上大脑中丰富的CaSR，可能会从根本上改变我们对大麻素作用机制的理解。这项建议的目的是确定CaSR是否是大麻类药物作用的重要途径，以及大脑CaSR是否直接被大麻类物质激活。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的CaSR功能方面的专业知识。这些具体目标的成功完成将成为CASR对大麻类物质反应的特征，有助于了解CASR的更广泛影响范围，并极大地改变这一领域的思维方式。我们的理论基础是，一种新的和流行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行为。此外，区分大麻素的各种作用可转化为确定一类新的药物，促进大麻成瘾和几种神经疾病的治疗。

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.