Kurose Hitoshi
Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University.
Yakugaku Zasshi. 2022;142(10):1091-1101. doi: 10.1248/yakushi.22-00087.
It is well-established that G protein-coupled receptors (GPCRs) transduce signals into cells using G proteins as intermediary molecules. β-Arrestins are molecules involved in regulating GPCRs; however, it has recently been reported that β-arrestins can also mediate signaling through GPCRs. Signaling through G proteins or β-arrestins can be activated selectively using specific agonists; of the latter, those that can selectively activate either G proteins or β-arrestins are called biased agonists. The clinical use of biased agonists could potentially induce fewer side effects. However, partial agonists can also explain the mechanism of G protein-biased agonists; thus, appropriate assay systems must be considered. Endogenous agonists are known to bind to orthosteric and allosteric sites in the agonist binding site, and the allosteric site is associated with the activity of biased agonists. This current review presents a detailed discussion of biased agonists.
众所周知，G蛋白偶联受体（GPCRs）利用G蛋白作为中间分子将信号转导至细胞内。β-抑制蛋白是参与调节GPCRs的分子；然而，最近有报道称β-抑制蛋白也可通过GPCRs介导信号传导。使用特定激动剂可选择性激活通过G蛋白或β-抑制蛋白的信号传导；对于后者，那些能够选择性激活G蛋白或β-抑制蛋白的激动剂被称为偏向激动剂。偏向激动剂的临床应用可能会减少副作用。然而，部分激动剂也可以解释G蛋白偏向激动剂的机制；因此，必须考虑合适的检测系统。已知内源性激动剂可结合激动剂结合位点的正构和变构位点，且变构位点与偏向激动剂的活性相关。本综述对偏向激动剂进行了详细讨论。
