Cannabinoid Modulation of Cell Function

描述（由申请人提供）：这是一份NIDA高级科学家奖的申请。我研究的主要目标是了解大麻素（大麻的主要精神活性成分）的急性和慢性作用的机制。我的研究重点是CB1（神经元）和CB2（“外周”）大麻素受体的功能和调节。大麻素，作用于CB1受体是离子通道功能的有效调节剂。与这些作用一致，有效的大麻素降低神经元兴奋性并抑制神经递质释放。有趣的是，内源性大麻素通过CB1受体抑制神经传递并介导多种形式的短期和长期神经元可塑性-部分通过非离子通道信号通路。CB2受体的激活缺乏明显的精神活性，最近被证明与镇痛、骨骼生长和动脉粥样硬化等多种过程有关，并作为潜在的治疗靶点受到密切关注。在接下来的五年里，我们将继续在分子和遗传水平上进行研究，强调以下具体目标。对大麻素的行为耐受是由于CB1受体磷酸化吗？是否有可能确定CB1和CB2激动剂引起很少的脱敏？二聚化在CB1和CB2受体的信号传导中起什么作用？CB1受体信号传导速度的决定因素是什么？第三种大麻素受体GPR55在大麻素作用中的作用是什么？实现这些目标将大大提高我们对大麻素细胞作用的理解。为了实现这些雄心勃勃的目标，我召集了一群合作者和顾问，他们的专业知识与我实验室目前的专业知识相辅相成。三个事实强调了在分子水平上对大麻素受体功能有深入了解的重要性。1. 长期使用大麻是一个重大的社会问题。2. 我们需要对大麻素受体激活的细胞效应有一个坚定的理解，以解释其治疗操作可能带来的好处。3. 我们对内源性大麻素在健康或病变组织中的生理作用知之甚少。

DESCRIPTION (provided by applicant): This is an application for a NIDA senior scientist award. The primary goal of my research is to understand the mechanisms underlying the acute and chronic effects of cannabinoids (the principal psychoactive constituents of cannabis). My studies are focused on the function and regulation of the CB1 (neuronal) and CB2 ("peripheral") cannabinoid receptors. Cannabinoids, acting at CB1 receptors are potent modulators of ion channel function. Consistent with these actions, efficacious cannabinoids decrease neuronal excitability and inhibit neurotransmitter release. Interestingly, endogenous cannabinoids acting via CB1 receptors inhibit neurotransmission and mediate several forms of short and long-term neuronal plasticity-in part through non-ion channel signaling pathways. CB2 receptors, whose activation is devoid of apparent psychoactivity, have recently been shown to be involved in processes as diverse as analgesia, bone growth, and atherosclerosis, and are receiving intense scrutiny as potential therapeutic targets. Over the next five years we will continue our studies at the molecular and genetic level, emphasizing the following specific aims. Is behavioral tolerance to cannabinoids due to CB1 receptor phosphorylation? Is it possible to identify CB1 and CB2 agonists that cause little desensitization? What role does dimerization have in the signaling of CB1 and CB2 receptors? What are the determinants of the speed of CB1 receptor signaling? What is the role of GPR55, a third cannabinoid receptor, in cannabinoid action? Accomplishing these goals will significantly advance our understanding of the cellular actions of cannabinoids. To accomplish these ambitious goals I have assembled a group of collaborators and consultants whose expertise complements that currently in place in my laboratory. Three facts underscore the importance of having a solid understanding of cannabinoid receptor function at the molecular level. 1. Chronic cannabis use is a significant social issue. 2. We need a firm understanding of the cellular effects of cannabinoid receptor activation to interpret the possible benefits of their therapeutic manipulation. 3. We know little about the physiological role of endogenous cannabinoids in healthy or diseased tissues.