Chemokines signal through classical G protein-coupled receptors (GPCRs) to induce cell migration during development, immune homeostasis and multiple diseases. Over the last decade a subfamily of atypical chemokine receptors (ACKRs) was delineated from GPCRs based on their inability to trigger conventional G protein signaling or mediate cell migration in response to chemokines. These receptors nevertheless play an important role within the chemokine system by sequestering, transporting or internalizing chemokines thereby regulating their availability and shaping their gradients. GPR182, the recently deorphanized chemokine receptor, shares about 30% of sequence similarity with its closest relative ACKR3. GPR182 is mainly expressed on endothelial cells and was proposed to act as a scavenger regulating the availability of a large set of chemokines from the CXC, CC and XC families and to act cooperatively with ACKR3 and ACKR4. Unlike other ACKRs, GPR182 was shown to have a strong constitutive interaction with β-arrestins that is required for intracellular receptor trafficking and chemokine scavenging. Chemokine ligation of GPR182 has no additional detectable impact on β-arrestin recruitment. Genetic ablation of GPR182 affects spleen size, myelopoiesis, and serum chemokine levels, indicating its role in chemokine homeostasis and immune regulation. GPR182 was also reported to regulate immune responses to bloodborne antigens and tumorigenesis. Taken together, compelling cumulative evidence indicates that GPR182 does not trigger G protein-mediated signaling but acts as a scavenger for chemokines in vitro and in vivo strongly supporting its inclusion as ACKR5 in the systematic nomenclature of chemokine receptors. Significance Statement The summarized presented findings strongly support the designation of GPR182 as ACKR5 and its formal inclusion in the family of atypical chemokine receptors.

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国际基础和临床药理学联合会。CXVIII. 包括 ACKR5 在内的非典型趋化因子受体命名法更新。


趋化因子通过经典的 G 蛋白偶联受体 （GPCR） 发出信号，在发育、免疫稳态和多种疾病过程中诱导细胞迁移。在过去十年中，非典型趋化因子受体 （ACKRs） 的一个亚家族与 GPCRs 被划分出来，因为它们无法触发常规 G 蛋白信号传导或介导响应趋化因子的细胞迁移。然而，这些受体通过隔离、运输或内化趋化因子，从而调节它们的可用性并塑造它们的梯度，在趋化因子系统中发挥着重要作用。GPR182 是最近去孤儿化的趋化因子受体，与其最近的亲戚 ACKR3 具有约 30% 的序列相似性。GPR182 主要在内皮细胞上表达，并被提议作为清除剂调节来自 CXC、CC 和 XC 家族的大量趋化因子的可用性，并与 ACKR3 和 ACKR4 协同作用。与其他 ACKR 不同，GPR182 被证明与细胞内受体运输和趋化因子清除所需的β-抑制蛋白具有很强的组成型相互作用。GPR182 的趋化因子连接对 β-arrestin 募集没有额外的可检测影响。GPR182 的基因消融会影响脾脏大小、骨髓生成和血清趋化因子水平，表明其在趋化因子稳态和免疫调节中的作用。据报道，GPR182 可调节对血源性抗原和肿瘤发生的免疫反应。综上所述，令人信服的累积证据表明，GPR182 不会触发 G 蛋白介导的信号传导，但在体外和体内充当趋化因子的清除剂，强烈支持其作为 ACKR5 包含在趋化因子受体的系统命名中。 意义声明 总结提出的研究结果强烈支持将 GPR182 指定为 ACKR5 并将其正式纳入非典型趋化因子受体家族。