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首页> 外文期刊>Molecular and Cellular Biology >Insulin Induces Heterologous Desensitization of G Protein-Coupled Receptor and Insulin-Like Growth Factor I Signaling by Downregulating β-Arrestin-1
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Insulin Induces Heterologous Desensitization of G Protein-Coupled Receptor and Insulin-Like Growth Factor I Signaling by Downregulating β-Arrestin-1

机译：胰岛素通过下调β-Arrestin-1诱导G蛋白偶联受体和胰岛素样生长因子I信号的异源脱敏

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β-Arrestin-1 mediates agonist-dependent desensitization and internalization of G protein-coupled receptors (GPCRs) and is also essential for GPCR mitogenic signaling. In addition, insulin-like growth factor I receptor (IGF-IR) endocytosis is facilitated by β-arrestin-1, and internalization is necessary for IGF-I-stimulated mitogen-activated protein (MAP) kinase activation. Here, we report that treatment of cells for 12 h with insulin (100 ng/ml) induces an ～50% decrease in cellular β-arrestin-1 content due to ubiquitination of β-arrestin-1 and proteosome-mediated degradation. This insulin-induced decrease in β-arrestin-1 content was blocked by inhibition of phosphatidylinositol-3 kinase (PI-3 kinase) and MEK with wortmannin and PD98059, respectively. We also found a marked decrease in the association of β-arrestin-1 with the IGF-IR and a 55% inhibition of IGF-I-stimulated MAP kinase phosphorylation. In insulin-treated, β-arrestin-1-downregulated cells, there was complete inhibition of lysophosphatidic acid (LPA) or isoproterenol (ISO)-stimulated MAP kinase phosphorylation. This was associated with a decrease in β-arrestin-1 association with the β2-AR as well as a decrease in β-arrestin-1-Src and Src-β2-AR association. Ectopic expression of wild-type β-arrestin-1 in insulin-treated cells in which endogenous β-arrestin-1 had been downregulated rescued IGF-I- and LPA-stimulated MAP kinase phosphorylation. In conclusion, we found the following. (i) Chronic insulin treatment leads to enhanced β-arrestin-1 degradation. (ii) This downregulation of endogenous β-arrestin-1 is associated with decreased IGF-I-, LPA-, and ISO-mediated MAP kinase signaling, which can be rescued by ectopic expression of wild-type β-arrestin-1. (iii) Finally, these results describe a novel mechanism for heterologous desensitization, whereby insulin treatment can impair GPCR signaling, and highlight the importance of β-arrestin-1 as a target molecule for this desensitization mechanism.
机译：β-Arrestin-1介导激动剂依赖性的G蛋白偶联受体（GPCR）脱敏和内在化，并且对于GPCR有丝分裂信号传导也是必不可少的。此外，β-arrestin-1可促进胰岛素样生长因子I受体（IGF-IR）的内吞作用，而内在化是IGF-I刺激的丝裂原活化蛋白（MAP）激酶活化所必需的。在这里，我们报道用胰岛素（100 ng / ml）处理细胞12 h会导致细胞β-arrestin-1含量降低约50％，这是由于β-arrestin-1的泛素化和蛋白体介导的降解。分别由渥曼青霉素和PD98059抑制磷脂酰肌醇-3激酶（PI-3激酶）和MEK抑制了胰岛素诱导的β-arrestin-1含量降低。我们还发现，β-arrestin-1与IGF-IR的结合显着降低，并且对IGF-I刺激的MAP激酶磷酸化有55％的抑制作用。在胰岛素治疗的β-arrestin-1下调的细胞中，溶血磷脂酸（LPA）或异丙肾上腺素（ISO）刺激的MAP激酶磷酸化被完全抑制。这与β-arrestin-1与β 2 -AR的缔合减少以及β-arrestin-1-Src和Src-β 2 -AR关联。在胰岛素处理的细胞中野生型β-arrestin-1的异位表达，其中内源性β-arrestin-1已被下调，从而挽救了IGF-1和LPA刺激的MAP激酶磷酸化。总之，我们发现了以下内容。 （i）慢性胰岛素治疗导致β-arrestin-1降解增强。 （ii）内源性β-arrestin-1的这种下调与IGF-I-，LPA-和ISO介导的MAP激酶信号降低有关，可以通过异位表达野生型β-arrestin-1来挽救。 （iii）最后，这些结果描述了异源脱敏的新机制，从而胰岛素治疗可损害GPCR信号传导，并突出了β-arrestin-1作为该脱敏机制的靶分子的重要性。

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