星形胶质细胞CB1大麻素受体调控神经元活动和学习记忆作用的信号途径

Cannabinoid receptors, consisting of type 1 and 2 receptors (CB1R and CB2R), are members of the GPCR family. CB1Rs are widely distributed in the CNS, not only in the neurons, but also in the glia, mainly astrocytes. It is generally accepted that neuronal CB1R is coupled to inhibitory G protein, Gi, while CB1R may also couple to other types of G proteins. Cannabinoids prospectively exhibit great medical therapeutic potential. However, different sources of cannabinoids may produce paradoxical actions, such as benefit or damage on synaptic transmission and plasticity, learning and memory, through activation on neuronal or astrocytic CB1Rs. Difference in G protein coupling to CB1Rs possibly underlies paradoxical actions of cannabinoids via CB1Rs on different cell types. It is unclear that whhich G proteins are coupled to astrocyte CB1Rs and functional role of astrocyte CB1R-G protein signaling. This project will employ methods including electrophysiology, molecular biology, cellular biology and behavioral test, to disclose G protein signaling pathways of astrocyte CB1Rs, and to clarify its action on synaptic transmission and plasticity, learning and memory. The aim is to provide new understandings on the functional mechanism of cannabinoid receptor, in order to give rise to more specific new strategy for the development of therapeutic drugs targeting on cannabinoid system.

大麻素受体包括CB1受体和CB2受体，均是G蛋白偶联受体。CB1受体广泛表达在中枢神经系统，即表达在神经元，也表达在胶质细胞，尤其是星形胶质细胞。一般认为，神经元CB1受体偶联抑制性G蛋白Gi，但研究认为CB1受体也可能偶联其它G蛋白。虽然大麻素被认为具有潜在的广阔医学应用前景，但不同来源的大麻素通过神经元或胶质细胞的大麻素受体，对突触传递和可塑性、学习记忆等可产生迥异的保护或损害作用。大麻素作用的多面性可能与大麻素受体在不同类型的细胞上，偶联不同的G蛋白信号途径有关。目前，星形胶质细胞CB1受体偶联的G蛋白信号途径还不清楚，本课题拟应用电生理、分子生物学、细胞生物学和动物行为学等方法，解析星形胶质细胞CB1受体的G蛋白偶联信号途径，及其在调控突触传递和可塑性、学习记忆等过程中作用，以揭示大麻素受体对机体的新的作用机制，给以大麻素系统为靶点的药物开发或不良作用防治提供新的、更加特异的策略。

大麻素包括内源性大麻素、外源性大麻素和化学合成大麻素。大麻素对疼痛、炎症、恶性肿瘤、神经退变性疾病、自身免疫性神经疾病、癫痫、自闭症、抑郁症、肥胖等多种疾病有潜在的广阔医学应用前景，但大麻素也会引起成瘾、学习记忆损害、恶心、头痛等不良作用。大麻素受体是G蛋白偶联受体，脑内表达最广泛的大麻素受体是CB1型大麻素受体，即表达在神经元，也表达在胶质细胞，尤其是星形胶质细胞。一般认为，CB1受体偶联的是抑制性G蛋白Gi，但研究认为CB1受体也可能偶联Gq蛋白。大麻素作用的多面性可能与大麻素受体在不同类型的细胞上偶联不同的G蛋白及其下游信号途径有关。星形胶质细胞CB1受体偶联的G蛋白及其下游信号途径及作用还不清楚。我们用细胞培养、转基因动物、分子生物学、钙成像和动物行为学等方法，研究发现了外源性大麻素CP55940可作用于星形胶质细胞CB1受体，通过Gq–PLC 和Gβγ–COX-2两种不同的信号途径分别介导Ca2+–ATP的释放和COX-2的表达。前者有利于改善抑郁样行为，后者则诱发学习记忆障碍和条件性位置厌恶。该结果解析了星形胶质细胞CB1受体的不同信号途径和相应的生理病理意义，为大麻素治疗作用的利用和副作用的防治提供了重要的理论基础。