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首页> 美国卫生研究院文献>Molecular Pharmacology >C-X-C Motif Chemokine Receptor 3 Splice Variants Differentially Activate Beta-Arrestins to Regulate Downstream Signaling Pathways
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C-X-C Motif Chemokine Receptor 3 Splice Variants Differentially Activate Beta-Arrestins to Regulate Downstream Signaling Pathways

机译：C-X-C母体趋化因子受体3剪接变体差异激活β-抑制蛋白以调节下游信号通路

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摘要

Biased agonism, the ability of different ligands for the same receptor to selectively activate some signaling pathways while blocking others, is now an established paradigm for G protein-coupled receptor signaling. One group of receptors in which endogenous bias is critical is the chemokine system, consisting of over 50 ligands and 20 receptors that bind one another with significant promiscuity. We have previously demonstrated that ligands for the same receptor can cause biased signaling responses. The goal of this study was to identify mechanisms that could underlie biased signaling between different receptor splice variants. The C-X-C motif chemokine receptor 3 (CXCR3) has two splice variants, CXCR3A and CXCR3B, which differ by 51 amino acids at its N-terminus. Consistent with an earlier study, we found that C-X-C motif chemokine ligands 4, 9, 10, and 11 all activated Gαi at CXCR3A, while at CXCR3B these ligands demonstrated no measurable Gαi or Gαs activity. β-arrestin (βarr) was recruited at a reduced level to CXCR3B relative to CXCR3A, which was also associated with differences in βarr2 conformation. βarr2 recruitment to CXCR3A was attenuated by both G protein receptor kinase (GRK) 2/3 and GRK5/6 knockdown, while only GRK2/3 knockdown blunted recruitment to CXCR3B. Extracellular regulated kinase 1/2 phosphorylation downstream from CXCR3A and CXCR3B was increased and decreased, respectively, by βarr1/2 knockout. The splice variants also differentially activated transcriptional reporters. These findings demonstrate that differential splicing of CXCR3 results in biased responses associated with distinct patterns of βarr conformation and recruitment. Differential splicing may serve as a common mechanism for generating biased signaling and provides insights into how chemokine receptor signaling can be modulated post-transcriptionally.
机译：偏置激动，即同一受体的不同配体选择性激活某些信号传导通路而阻断其他信号通路的能力，现已成为G蛋白偶联受体信号传导的既定范例。趋化因子系统是其中内源性偏向至关重要的一组受体，它由50多个配体和20个彼此显着混杂的受体组成。先前我们已经证明，同一受体的配体会引起信号传导反应偏向。这项研究的目的是确定可能是不同受体剪接变体之间的信号转导基础的机制。 C-X-C基序趋化因子受体3（CXCR3）具有两个剪接变体CXCR3A和CXCR3B，它们的N端相差51个氨基酸。与早期的研究一致，我们发现C-X-C基序趋化因子配体4、9、10和11在CXCR3A上均激活了Gαi，而在CXCR3B上，这些配体没有显示可测量的Gαi或Gαs活性。相对于CXCR3A，β-arrestin（βarr）的水平降低至CXCR3B，这也与βarr2构象的差异有关。 Gar蛋白受体激酶（GRK）2/3和GRK5 / 6敲低减弱了向CXCR3A的βarr2募集，而只有GRK2 / 3敲低降低了CXCR3B的募集。通过βarr1/ 2敲除分别增加和减少了CXCR3A和CXCR3B下游的细胞外调节激酶1/2磷酸化。剪接变体还差异地激活转录报道分子。这些发现表明，CXCR3的不同剪接导致与βarr构象和募集的不同模式相关的偏倚应答。差异剪接可作为产生偏向信号的通用机制，并提供有关如何在转录后调节趋化因子受体信号的见解。

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