G protein‐coupled receptors (GPCRs) represent a major group of drug targets with tremendous pharmacological value. Signals arising from GPCRs are primarily transduced via two functional components of their corresponding G proteins, the Gα subunit and the Gβγ dimer that dissociate from each other upon activation of the heterotrimer (Gαβγ). The Gβγ dimer has become an increasingly popular subject in GPCR signaling, owing to its numerous effectors and notable roles in signal integration. Because Gβγ dimers participate in a wide range of intracellular processes that regulate cellular physiology, they are often implicated in the pathology of various diseases. Yet, one caveat to the current ‘Dissociation Model’ on GPCR signaling is that unequivocal Gβγ signals are biasedly detected with G_i/o‐coupled receptors, while Gβγ signals from G_s‐ or G_q‐coupled receptors seem to play an auxiliary role. In this review, we revisit the evidence for or against the ‘Dissociation Model’ and discuss in detail several hypotheses that may explain such disparity and provide alternative interpretations to accommodate the ‘biased Gβγ signals’ observed in different biological systems. The issue of whether unique combinations of Gβγ dimer can confer signaling specificity is also discussed in the context of physiological relevance.

中文翻译：

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从Gβγ信号转导的角度重新审视G蛋白活化的“解离模型”

G蛋白偶联受体（GPCR）代表了一大类具有巨大药理价值的药物靶标。GPCR产生的信号主要通过其相应G蛋白的两个功能成分进行转导，即Gα亚基和Gβγ二聚体，它们在异源三聚体（Gαβγ）激活后会彼此解离。Gβγ二聚体由于其众多的效应子和在信号整合中的显着作用，已成为GPCR信号传导中越来越受欢迎的主题。因为Gβγ二聚体参与调节细胞生理的多种细胞内过程，所以它们通常与各种疾病的病理学有关。然而，当前关于GPCR信号的“解离模型”的一个警告是，G _{i / o}偏向地检测到明确的Gβγ信号_。偶联受体，而来自G _s或G _q偶联受体的Gβγ信号似乎起辅助作用。在这篇综述中，我们回顾了支持或反对“解离模型”的证据，并详细讨论了一些假说，这些假说可以解释这种差异，并提供其他解释以适应在不同生物系统中观察到的“偏向Gβγ信号”。在生理相关性的背景下，还讨论了Gβγ二聚体的独特组合是否可以赋予信号传导特异性的问题。