Biased Agonism as a Mechanism for Differential Signaling by Chemokine Receptors
Biased Agonism as a Mechanism for Differential Signaling by Chemokine Receptors
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DOI：
10.1074/jbc.m113.479113
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发表时间：
2013-12-06
影响因子：
4.8
通讯作者：
Wehrman, Tom S.
中科院分区：
文献类型：
--
作者：
Rajagopal, Sudarshan;Bassoni, Daniel L.;Wehrman, Tom S.
背景：趋化因子被认为通过它们共同的受体以多余的方式发挥作用。结果：趋化因子对G蛋白和抑制素的作用不同，导致趋化作用谱不同。结论：趋化因子可以作为受体上的偏向激动剂，导致不同的功能反应，而不是多余的反应。意义：有偏见的激动剂在生物信号传递中起着重要作用。趋化因子表现出相当程度的混杂，多个配体和受体共有，这一现象被认为是其生化冗余的基础。它们的受体是一个更大的七跨膜受体超家族的一部分，通常被称为G蛋白偶联受体，已被证明能够以不同的效率向其多个下游信号通路发出信号，这种现象被称为偏向激动症。偏向激动症最初被报道为一种合成配体的现象，这种信号在生物学上的流行程度和重要性尚不清楚。在这里，为了评估趋化因子针对同一受体的不同信号转导可能存在的偏向激动剂的存在，我们对一组具有多个内源性配体的趋化因子受体进行了详细的药理学分析，方法是G蛋白信号转导、-arrestin募集和受体内化。我们发现，针对同一受体的趋化因子在G蛋白或arrestin介导的信号转导或受体内化方面的有效性可以显示出显著的差异。这种配体偏向与白细胞迁移的变化相关，与其配体诱导的这些受体下游信号传递的不同机制相一致。这些发现表明，偏激是一种常见的、可能在进化上保守的生物学机制，可以通过相同的受体产生不同的信号模式，以响应不同的内源配体。
Background: Chemokines have been thought to act in a redundant fashion through their shared receptors. Results: Chemokines can display different efficacies for G proteins and -arrestins, resulting in different chemotactic profiles. Conclusion: Chemokines can behave as biased agonists at their receptors, leading to functionally distinct, not redundant, responses. Significance: Biased agonism plays an important role in biological signaling.Chemokines display considerable promiscuity with multiple ligands and receptors shared in common, a phenomenon that is thought to underlie their biochemical redundancy. Their receptors are part of a larger seven-transmembrane receptor superfamily, commonly referred to as G protein-coupled receptors, which have been demonstrated to be able to signal with different efficacies to their multiple downstream signaling pathways, a phenomenon referred to as biased agonism. Biased agonism has been primarily reported as a phenomenon of synthetic ligands, and the biologic prevalence and importance of such signaling are unclear. Here, to assess the presence of biased agonism that may underlie differential signaling by chemokines targeting the same receptor, we performed a detailed pharmacologic analysis of a set of chemokine receptors with multiple endogenous ligands using assays for G protein signaling, -arrestin recruitment, and receptor internalization. We found that chemokines targeting the same receptor can display marked differences in their efficacies for G protein- or -arrestin-mediated signaling or receptor internalization. This ligand bias correlates with changes in leukocyte migration, consistent with different mechanisms underlying the signaling downstream of these receptors induced by their ligands. These findings demonstrate that biased agonism is a common and likely evolutionarily conserved biological mechanism for generating qualitatively distinct patterns of signaling via the same receptor in response to different endogenous ligands.