Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) are common drug targets and canonically couple to specific Gα protein subtypes and β-arrestin adaptor proteins. G protein- and β-arrestin-mediated signaling have been considered separable. We show GPCRs promote a direct interaction between Gαi protein subtype family members and β-arrestins, regardless of their canonical Gαi protein subtype coupling. Gαi:β-arrestin complexes bound extracellular signal-regulated kinase (ERK) and their disruption impaired both ERK activation and cell migration, consistent with β-arrestins requiring a functional interaction with Gαi for certain signaling events. These results introduce a GPCR signaling mechanism distinct from canonical G protein activation in which GPCRs cause the formation of Gαi:β-arrestin signaling complexes.

中文翻译：

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G蛋白偶联受体对Gαi和β-arrestin的非典型支架

异源三聚体鸟嘌呤核苷酸结合蛋白 (G 蛋白) 偶联受体 (GPCR) 是常见的药物靶标，并且与特定的 Gα 蛋白亚型和 β-抑制蛋白衔接蛋白典型偶联。G 蛋白和 β-arrestin 介导的信号传导被认为是可分离的。我们显示 GPCR 促进 Gαi 蛋白亚型家族成员和 β-抑制蛋白之间的直接相互作用，无论它们的经典 Gαi 蛋白亚型偶联如何。Gαi:β-arrestin 复合物与细胞外信号调节激酶 (ERK) 结合，它们的破坏会损害 ERK 活化和细胞迁移，这与 β-arrestin 需要与 Gαi 进行功能性相互作用才能进行某些信号传导事件一致。这些结果引入了与典型 G 蛋白激活不同的 GPCR 信号传导机制，其中 GPCR 导致 Gαi:β-抑制蛋白信号传导复合物的形成。