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CB1R independent effects of cannabinoids on synaptic physiology in the CNS.

大麻素对中枢神经系统突触生理学的 CB1R 独立影响。

基本信息

批准号：
8225252
负责人：
CHARLES J FRAZIER
金额：
$ 18.31万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2015-02-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): This is a basic science proposal designed to use in vitro electrophysiological and optical techniques to further our understanding of an extremely unusual form of cannabinoid dependent signaling discovered in my lab. Specifically, we have observed that cannabinoid receptor agonists potentiate action potential independent release of GABA in the dentate gyrus through a cannabinoid type I (CB1) receptor independent mechanism. Although recent years have brought an enormous wealth of new information about the specific roles of endogenous cannabinoids in CNS physiology, the effect of cannabinoid receptor agonists that we have discovered appears to be unique in numerous respects. First, it does not depend on activation of CB1, CB2, or vanilloid type I receptors, and is still present in CB1-/- animals. Second, it clearly modulates action potential independent exocytotic events without altering action potential dependent events, and third, it ultimately results in the facilitation (rather than inhibition) of exocytosis. While our preliminary data represent significant progress towards characterizing a new role for cannabinoids in CNS physiology, many fundamental questions regarding this new phenomenon remain. Therefore this proposal requests funds to continue our investigation in this area through implementation of two Specific Aims. Aim 1 will test the hypothesis that cannabinoid mediated facilitation of action potential independent exocytosis depends on a specific ligand receptor interaction with an as yet unidentified GPCR. Specifically, we hypothesize that a G1s -> AC -> cAMP -> PKA signaling cascade is involved. Aim 2 will test the hypothesis that anandamide or one of its metabolites will be the most effective endogenously available ligand for facilitation of action potential independent release, and that the best agonists will work well within a physiologically relevant concentration range. Collectively, these Aims are designed to provide data that have the potential to clearly establish the significance of our findings for the cannabinoid field, and that will directly facilitate a longer term and larger scale investigation of the phenomenon. PUBLIC HEALTH RELEVANCE: Nearly all the known central effects of endogenous cannabinoids are thought to be mediated by activation of a single type of receptor, the CB1 cannabinoid receptor. We have recently discovered a highly novel form of cannabinoid mediated signaling that does not depend on CB1 receptor activation, and that has unique effects on CNS physiology. The current proposal is designed to address several fundamental questions about this new signaling system that we hope will ultimately establish the overall significance (and potential) of the finding.

描述（由申请人提供）：这是一项基础科学提案，旨在利用体外电生理学和光学技术来进一步了解我的实验室发现的一种极其不寻常的大麻素依赖性信号传导形式。具体来说，我们观察到大麻素受体激动剂通过 I 型大麻素 (CB1) 受体独立机制增强齿状回中 GABA 的动作电位独立释放。尽管近年来关于内源性大麻素在中枢神经系统生理学中的具体作用带来了大量新信息，但我们发现的大麻素受体激动剂的作用在许多方面似乎都是独特的。首先，它不依赖于 CB1、CB2 或 I 型香草醛受体的激活，并且仍然存在于 CB1-/- 动物中。其次，它清楚地调节动作电位独立的胞吐事件，而不改变动作电位依赖性事件，第三，它最终导致胞吐作用的促进（而不是抑制）。虽然我们的初步数据代表了大麻素在中枢神经系统生理学中新作用的重大进展，但有关这一新现象的许多基本问题仍然存在。因此，该提案要求提供资金，通过实施两个具体目标来继续我们在这一领域的调查。目标 1 将检验大麻素介导的动作电位独立胞吐作用的促进取决于特定配体受体与尚未鉴定的 GPCR 的相互作用。具体来说，我们假设涉及 G1s -> AC -> cAMP -> PKA 信号级联。目标 2 将检验以下假设：anandamide 或其代谢物之一将是促进动作电位独立释放的最有效的内源性配体，并且最佳激动剂将在生理相关浓度范围内发挥良好作用。总的来说，这些目标旨在提供数据，这些数据有可能清楚地确定我们的研究结果对大麻素领域的重要性，并将直接促进对该现象进行更长期和更大规模的调查。公共健康相关性：几乎所有已知的内源性大麻素的中心效应都被认为是由单一类型的受体（CB1 大麻素受体）的激活介导的。我们最近发现了一种高度新颖的大麻素介导的信号传导形式，它不依赖于 CB1 受体激活，并且对中枢神经系统生理学具有独特的影响。目前的提案旨在解决有关这个新信号系统的几个基本问题，我们希望这些问题最终能够确定该发现的总体意义（和潜力）。