Jong Yuh-Jiin I, Sergin Ismail, Purgert Carolyn A, O'Malley Karen L
Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri.
Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri
Mol Pharmacol. 2014 Dec;86(6):774-85. doi: 10.1124/mol.114.094763. Epub 2014 Oct 17.
Although G protein-coupled receptors are primarily known for converting extracellular signals into intracellular responses, some receptors, such as the group 1 metabotropic glutamate receptor, mGlu5, are also localized on intracellular membranes where they can mediate both overlapping and unique signaling effects. Thus, besides "ligand bias," whereby a receptor's signaling modality can shift from G protein dependence to independence, canonical mGlu5 receptor signaling can also be influenced by "location bias" (i.e., the particular membrane and/or cell type from which it signals). Because mGlu5 receptors play important roles in both normal development and in disorders such as Fragile X syndrome, autism, epilepsy, addiction, anxiety, schizophrenia, pain, dyskinesias, and melanoma, a large number of drugs are being developed to allosterically target this receptor. Therefore, it is critical to understand how such drugs might be affecting mGlu5 receptor function on different membranes and in different brain regions. Further elucidation of the site(s) of action of these drugs may determine which signal pathways mediate therapeutic efficacy.
虽然G蛋白偶联受体主要以将细胞外信号转化为细胞内反应而闻名，但一些受体，如1型代谢型谷氨酸受体mGlu5，也定位于细胞内膜，在那里它们可以介导重叠和独特的信号效应。因此，除了“配体偏向”（即受体的信号传导方式可以从依赖G蛋白转变为不依赖G蛋白）之外，典型的mGlu5受体信号传导也会受到“定位偏向”（即它发出信号的特定膜和/或细胞类型）的影响。由于mGlu5受体在正常发育以及脆性X综合征、自闭症、癫痫、成瘾、焦虑、精神分裂症、疼痛、运动障碍和黑色素瘤等疾病中都发挥着重要作用，目前正在研发大量药物以变构方式作用于该受体。因此，了解此类药物如何影响不同膜和不同脑区的mGlu5受体功能至关重要。进一步阐明这些药物的作用位点可能会确定哪些信号通路介导治疗效果。
