Department of Pharmacology and Department of Physiology, Institute of Biomedicine, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Front Neurol Neurosci. 2021;45:91-102. doi: 10.1159/000514962. Epub 2021 May 28.
Orexin receptors (OXRs) are promiscuous G-protein-coupled receptors that signal via several G-proteins and, putatively, via other proteins. On which basis the signal pathways are selected and orchestrated is largely unknown. We also have an insufficient understanding of the kind of signaling that is important for specific types of cellular responses. OXRs are able to form complexes with several other G-protein-coupled receptors in vitro, and one possibility is that the complexing partners regulate the use of certain signal transducers. In the central nervous system neurons, the main acute downstream responses of OXR activation are the inhibition of K+ channels and the activation of the Na+/Ca2+ exchanger and non-selective cation channels of unknown identity. The exact nature of the intracellular signal chain between the OXRs and these downstream targets is yet to be elucidated, but the Gq-phospholipase C (PLC) protein kinase C pathway - which is a significant signaling pathway for OXRs in recombinant cells - may be one of the players in neurons. The Gq-PLC pathway may also, under certain circumstances, take the route to diacylglycerol lipase, which leads to the production of the potent endocannabinoid (eCB), 2-arachidonoyl glycerol, and thereby connects orexins with eCB signaling. In addition, OXRs have been studied in the context of neurodegeneration and cancer cell death. Overall, OXR signaling is complex, and it can change depending on the cell type and environment.
食欲素受体（OXRs）是一种混杂的 G 蛋白偶联受体，可通过几种 G 蛋白和潜在的其他蛋白发出信号。信号通路的选择和协调在很大程度上是未知的。我们对特定类型细胞反应中重要的信号类型也缺乏足够的了解。OXRs 能够在体外与几种其他 G 蛋白偶联受体形成复合物，一种可能性是，这些复合物伙伴调节某些信号转导器的使用。在中枢神经系统神经元中，OXR 激活的主要急性下游反应是抑制 K+通道，激活 Na+/Ca2+交换器和未知身份的非选择性阳离子通道。OXR 与这些下游靶标之间的细胞内信号链的确切性质尚未阐明，但 Gq-磷脂酶 C（PLC）蛋白激酶 C 途径 - 这是重组细胞中 OXR 的重要信号途径 - 可能是神经元中的一种途径。在某些情况下，Gq-PLC 途径也可能通向二酰基甘油脂肪酶，导致产生强效内源性大麻素（eCB），2-花生四烯酸甘油，从而将食欲素与 eCB 信号联系起来。此外，OXRs 已在神经退行性变和癌细胞死亡的背景下进行了研究。总体而言，OXR 信号很复杂，它可以根据细胞类型和环境而变化。
