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）：这是一项基础科学建议，旨在使用体外电生理学和光学技术来进一步了解我们实验室中发现的一种极为不寻常的大麻素依赖性信号的形式。具体而言，我们已经观察到，大麻素受体激动剂通过大麻素（CB1）受体独立的机制增强了齿状回中GABA的潜在独立释放。尽管近年来为内源性大麻素在中枢神经系统生理学中的特定作用带来了大量的新信息，但我们发现的大麻素受体激动剂的影响在许多方面似乎是独一无二的。首先，它不取决于CB1，CB2或Vanilloid I型受体的激活，并且仍然存在于CB1 - / - 动物中。其次，它清楚地调节了动作潜在的独立胞吐事件，而不会改变动作潜在的依赖性事件，第三，最终导致促进（而不是抑制）胞吐作用。尽管我们的初步数据代表着表征大麻素在中枢神经系统生理学中的新作用的重大进展，但有关这种新现象的许多基本问题仍然存在。因此，该提案要求资金通过实施两个特定目标来继续我们在这一领域进行调查。 AIM 1将检验以下假设：大麻素介导的作用促进作用潜在独立胞吐作用取决于特定的配体受体相互作用与尚未确定的GPCR。具体而言，我们假设涉及g1s-> AC-> CAMP-> PKA信号级联。 AIM 2将检验以下假设：anandamide或其一种代谢产物之一将是最有效的内生可用的配体，以促进动作潜在的独立释放，并且最佳的激动剂将在生理上相关的浓度范围内很好地工作。总的来说，这些目标旨在提供具有明确确定我们发现对大麻素场的意义的潜力的数据，这将直接促进对现象的长期和更大范围的研究。公共卫生相关性：几乎所有已知的内源性大麻素的中心作用都被认为是通过一种类型的受体CB1大麻素受体的激活来介导的。我们最近发现了一种高度新颖的大麻素介导的信号传导，不取决于CB1受体的激活，并且对CNS生理具有独特的影响。当前的提案旨在解决有关这种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整体意义（和潜在）。