Central calcium and cannabinoid signaling

中枢钙和大麻素信号传导

• 批准号: 8236613
• 负责人: Stephen M Smith
• 金额: $ 29.26万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236613
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Adverse effects; Affect; Agonist; Animal Model; Antiepileptic Agents; Area; Behavioral; Binding; Binding Sites; Biological Assay; Brain; CNR1 gene; CNR2 gene; Calcium; Calcium-Sensing Receptors; Cannabinoids; Cannabis; Cations; Cells; Chronic; Chronic Cancer Pain; Clinical effectiveness; Collaborations; Coupled; Data; Disease; Dissection; Dose-Limiting; Drug Addiction; Drug Design; Drug usage; Endocannabinoids; Environment; Excitatory Synapse; G-Protein-Coupled Receptors; Gilles de la Tourette syndrome; Huntington Disease; Knowledge; Ligands; Light; Link; Marijuana Dependence; Measures; Movement Disorders; Muscle; Mutant Strains Mice; Mutation; Neocortex; Nerve; Nervous system structure; Neurologic; Neurons; Nucleus solitarius; Patch-Clamp Techniques; Pathway interactions; Peripheral; Pharmaceutical Preparations; Probability; Protein Isoforms; Receptor Activation; Research; Signal Transduction; Slice; Spasm; Spinal cord injury; Synaptic Transmission; Synaptic plasticity; System; Testing; Thinking; Transfection; Translating; Work; addiction; anandamide; base; cannabinoid receptor; chronic pain; design; extracellular; fight against; improved; interest; mutant; nervous system disorder; neuronal excitability; novel; novel strategies; overexpression; patch clamp; receptor; receptor function; receptor structure function; receptor-mediated signaling; research study; response; voltage; wasting

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. PUBLIC HEALTH RELEVANCE: Cannabis is a commonly used drug that is associated with drug dependence, but has also been proposed as therapy for several illnesses including chronic pain, cancer and AIDS-related wasting. New improved treatments are needed 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 in the fight against drug dependence and many serious diseases.

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。这些具体目标的成功完成将表征CaSR对大麻素的反应，揭示CaSR更广泛的影响范围，并大大改变这一领域的思维。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。 公共卫生相关性：大麻是一种与药物依赖有关的常用药物，但也被提议用于治疗多种疾病，包括慢性疼痛，癌症和艾滋病相关的消耗。需要新的改进治疗方法，但这需要更好地了解大麻的作用机制。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，从而提高设计新疗法的机会，以帮助对抗药物依赖和许多严重疾病。