Department of Toxicology & Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
Department of Pharmacology, Vanderbilt University, 2200 Pierce Ave South, PRB, Rm. 417D, Nashville, TN, 37232, USA.
Neuropharmacology. 2024 Dec 15;261:110167. doi: 10.1016/j.neuropharm.2024.110167. Epub 2024 Sep 19.
GPCRs are inherently flexible molecules existing in an equilibrium of multiple conformations. Binding of GPCR agonists shifts this equilibrium. Certain agonists can increase the fraction of active-like conformations that predispose the receptor to coupling to a particular signal transducer or a select group of transducers. Such agonists are called biased, in contrast to balanced agonists that facilitate signaling via all transducers the receptor couples to. These biased agonists preferentially channel the signaling of a GPCR to particular G proteins, GRKs, or arrestins. Preferential activation of particular G protein or arrestin subtypes can be beneficial, as it would reduce unwanted on-target side effects, widening the therapeutic window. However, biasing GPCRs has two important limitations: a) complete bias is impossible due to inherent flexibility of GPCRs; b) receptor-independent functions of signal transducer proteins cannot be directly affected by GPCR ligands or differential receptor barcoding by GRK phosphorylation. This article is part of the Special Issue on "Ligand Bias".
G 蛋白偶联受体是具有内在灵活性的分子，存在于多种构象的平衡状态中。G 蛋白偶联受体激动剂的结合会使这种平衡发生转移。某些激动剂可以增加类似于活性的构象的分数，从而使受体更容易与特定的信号转导器或特定的转导器组结合。与促进通过受体结合的所有转导器进行信号传递的平衡激动剂相比，这种激动剂被称为偏向激动剂。这些偏向激动剂优先将 G 蛋白偶联受体的信号传递给特定的 G 蛋白、GRK 或 arrestin。特定 G 蛋白或 arrestin 亚型的优先激活可能是有益的，因为它可以减少不必要的靶标副作用，扩大治疗窗口。然而，G 蛋白偶联受体的偏向具有两个重要的局限性：a）由于 G 蛋白偶联受体的固有灵活性，完全偏向是不可能的；b）信号转导蛋白的受体独立功能不能被 G 蛋白偶联受体配体或 GRK 磷酸化的受体差异化编码直接影响。本文是“配体偏向”特刊的一部分。
