Reuptake and hydrolysis shape endocannabinoid signaling

再摄取和水解塑造内源性大麻素信号传导

• 批准号: 7090087
• 负责人: RICKA D COOPER
• 金额: $ 3.23万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7090087
• 关键词: amidohydrolases; anandamide; biological transport; brain metabolism; cannabinoids; cell communication molecule; eicosanoids; enzyme inhibitors; gamma aminobutyrate; interneurons; laboratory mouse; predoctoral investigator; pyramidal cells; voltage /patch clamp

DESCRIPTION (provided by applicant): The long-term objective of this work is to identify the regulatory mechanisms of endogenous cannabinoid signaling in the neocortex. The endocannabinoids (eCBs), of which N-arachidonyl ethanolamide (anandamide, AEA) and 2-arachidonyl glycerol (2-AG) are the best studied, are cleaved from phospholipid precursors and released on demand from principle cells. The eCBs are then rapidly taken into cells and hydrolyzed, but the role of inactivation in the kinetics of eCB synaptic transmission has not been investigated. Fatty acid amide hydrolase (FAAH) hydrolyzes both AEA and 2-AG in vitro, and both eCBs are thought to reenter cells through a temperature-dependent, saturable, and selective reuptake process. Specific pharmacologic agents are available to inhibit both FAAH and the reuptake process. The proposed experiments intend to make use of these agents, FAAH knockout mice, and whole-cell patch clamp techniques to investigate the role of FAAH (Aim 1) and reuptake (Aim 2) in endocannabinoid signaling between GABAergic interneurons and cortical Layer II/III pyramidal neurons.

描述（由申请人提供）：这项工作的长期目标是确定新皮质中内源性大麻素信号传导的调节机制。内源性大麻素 (eCB)，其中 N-花生四烯基乙醇酰胺 (anandamide，AEA) 和 2-花生四烯基甘油 (2-AG) 是研究得最好的，它们从磷脂前体中裂解出来，并根据主细胞的需要释放。然后 eCB 被快速摄入细胞并水解，但失活在 eCB 突触传递动力学中的作用尚未得到研究。脂肪酸酰胺水解酶 (FAAH) 在体外水解 AEA 和 2-AG，并且两种 eCB 被认为通过温度依赖性、可饱和和选择性再摄取过程重新进入细胞。特定的药物可抑制 FAAH 和再摄取过程。拟议的实验旨在利用这些药物、FAAH 敲除小鼠和全细胞膜片钳技术来研究 FAAH（目标 1）和再摄取（目标 2）在 GABA 能中间神经元和皮质 II/III 层之间的内源性大麻素信号传导中的作用锥体神经元。