The molecular associations in clathrin-coated pit regulate β-arrestin-mediated MAPK signaling downstream of μ-opioid receptor
The molecular associations in clathrin-coated pit regulate β-arrestin-mediated MAPK signaling downstream of μ-opioid receptor
复制标题
网格蛋白包被的坑中的分子关联调节μ-阿片受体下游β-抑制蛋白介导的MAPK信号传导
DOI：
10.1016/j.bbrc.2022.11.098
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发表时间：
2023
影响因子：
3.1
通讯作者：
Shimizu Satoshi
中科院分区：
文献类型：
--
作者：
Shiraki Atsuko;Shimizu Satoshi
人们认为μ-阿片受体（MOPs）激活G蛋白介导的镇痛通路和β-arrestin 2介导的副作用通路;然而，仅最低程度地将β-arrestin 2募集到MOPs的配体也可能引起阿片副作用。此外，在缺乏β-arrestin 2或表达不募集β-arrestin 2的磷酸化缺陷型MOPs的突变小鼠中诱导了此类副作用。这些发现提出了一个关键问题，即β-arrestin 2募集到MOP是否会引发副作用。在这里，我们表明β-arrestin 1和2是必不可少的有效激活Gi/o介导的MAPK信号在MOP。此外，β-arrestin介导的信号的大小与MOP的羧基端磷酸化的大小不相关，MOP的羧基端磷酸化的大小用于评估配体的β-arrestin偏倚。相反，在网格蛋白包被的小凹的形成中与β2-适应素和网格蛋白重链的分子缔合对于β-抑制蛋白激活MAPK信号传导是必需的。我们的研究结果提供了对G蛋白偶联受体介导的信号传导的见解，并进一步强调了内吞作用所需分子的积累对于激活细胞内信号传导至关重要的概念。
It has been thought that μ-opioid receptors (MOPs) activate the G protein-mediated analgesic pathway and β-arrestin 2-mediated side effect pathway; however, ligands that only minimally recruit β-arrestin 2 to MOPs may also cause opioid side effects. Moreover, such side effects have been induced in mutant mice lacking β-arrestin 2 or expressing phosphorylation-deficient MOPs that do not recruit β-arrestin 2. These findings raise the critical question of whether β-arrestin 2 recruitment to MOP triggers side effects. Here, we show that β-arrestin 1 and 2 are essential in the efficient activation of the Gi/o-mediated MAPK signaling at MOP. Moreover, the magnitude of β-arrestin-mediated signals is not correlated with the magnitude of phosphorylation of the carboxyl-terminal of MOP, which is used to evaluate the β-arrestin bias of a ligand. Instead, the molecular association with β2-adaptin and clathrin heavy chain in the formation of clathrin-coated pits is essential for β-arrestin to activate MAPK signaling. Our findings provide insights into G protein-coupled receptor-mediated signaling and further highlight a concept that the accumulation of molecules required for endocytosis is critical for activating intracellular signaling.