Lopes João P, Morató Xavier, Souza Carolina, Pinhal Cindy, Machado Nuno J, Canas Paula M, Silva Henrique B, Stagljar Igor, Gandía Jorge, Fernández-Dueñas Víctor, Luján Rafael, Cunha Rodrigo A, Ciruela Francisco
CNC-Center for Neurosciences and Cell Biology and Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
J Neurochem. 2015 Jul;134(1):135-46. doi: 10.1111/jnc.13109. Epub 2015 Apr 21.
GPR37 is an orphan G protein-coupled receptor mostly enriched in brain areas such as the cerebellum, striatum, and hippocampus. Identified as a substrate of parkin, GPR37 has been suggested to play a role in Parkinson's disease. Distributed throughout the brain, the function of GPR37, however, remains unknown. We now provide the first mapping of GPR37 within the hippocampus, where GPR37 is widely expressed and localized at the level of the extrasynaptic plasma membrane of dendritic spines, dendritic shafts, and axon terminals. GPR37 per se does not appear to play a role in learning and memory, since knocking out GPR37 (GPR37-KO) did not alter the performance in different hippocampal-related memory tasks. This is in agreement with slice electrophysiology experiments showing no differences both in short-term plasticity paired-pulse facilitation and long-term potentiation between WT and GPR37-KO mice. However, we report a potential functional interaction between GPR37 and adenosine A2A receptors (A2 A R) in the hippocampus, with A2 A R modulating the GPR37-associated phenotype. Thus, the absence of GPR37 appeared to sensitize mice to hippocampal A2 A R-mediated signaling, as observed by the effect of the A2 A R antagonist SCH58261 increasing synaptic depotentiation, reducing novel object recognition memory and reverting the anxiolytic effect of GPR37 deletion. Collectively, these findings afford insight into the localization and role of the orphan GPR37 within the hippocampus with potential involvement in A2 A R function (i.e., A2 A R sensitization). GPR37 is an orphan G protein-coupled receptor widely expressed in the hippocampus and localized at the level of the extrasynaptic plasma membrane of dendritic spines, dendritic shafts and axon terminals. This orphan receptor per se does not appear to directly control the learning and memory processes; however knocking-out GPR37 triggers anxiolytic-like effects and sensitizes mice to hippocampal A2A R-mediated signalling.
GPR37是一种孤儿G蛋白偶联受体，主要富集于小脑、纹状体和海马体等脑区。GPR37被鉴定为帕金蛋白的底物，有人认为它在帕金森病中起作用。然而，尽管GPR37分布于整个大脑，但其功能仍不清楚。我们现在首次绘制了GPR37在海马体中的分布图，GPR37在海马体中广泛表达，并定位于树突棘、树突轴和轴突终末的突触外质膜水平。GPR37本身似乎在学习和记忆中不起作用，因为敲除GPR37（GPR37基因敲除）并没有改变在不同海马体相关记忆任务中的表现。这与切片电生理实验结果一致，该实验表明野生型和GPR37基因敲除小鼠在短期可塑性配对脉冲易化和长期增强方面均无差异。然而，我们报告了海马体中GPR37与腺苷A2A受体（A2AR）之间存在潜在的功能相互作用，其中A2AR调节GPR37相关表型。因此，如A2AR拮抗剂SCH58261增加突触去增强、降低新物体识别记忆以及逆转GPR37缺失的抗焦虑作用所观察到的那样，GPR37的缺失似乎使小鼠对海马体A2AR介导的信号敏感。总的来说，这些发现有助于深入了解孤儿GPR37在海马体中的定位和作用，其可能参与A2AR功能（即A2AR敏化）。GPR37是一种孤儿G蛋白偶联受体，在海马体中广泛表达，并定位于树突棘、树突轴和轴突终末的突触外质膜水平。这种孤儿受体本身似乎并不直接控制学习和记忆过程；然而，敲除GPR37会引发抗焦虑样效应，并使小鼠对海马体A2AR介导的信号敏感。
