The orphan G-protein-coupled receptor 75 signaling is activated by the chemokine CCL5.
The orphan G-protein-coupled receptor 75 signaling is activated by the chemokine CCL5.
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DOI：
10.1111/jnc.14463
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发表时间：
2018-09
影响因子：
4.7
通讯作者：
Mocchetti I
中科院分区：
文献类型：
--
作者：
Dedoni S;Campbell LA;Harvey BK;Avdoshina V;Mocchetti I
趋化因子CCL5防止由淀粉样蛋白β以及人类免疫缺陷病毒病毒蛋白gp120和Tat介导的神经细胞死亡。由于CCL5与CCR5、CCR3和/或CCR1受体结合，目前尚不清楚这些受体中的哪一种在神经保护中发挥作用。事实上，CCL5在缺乏这些受体的细胞中也具有神经保护活性。CCL5可能与G蛋白偶联受体75(GPR75)结合，GPR75编码GQα家族的540个氨基酸的孤儿受体。在这项研究中，我们使用SH-SY5Y人神经母细胞瘤细胞来鉴定CCL5是否可以通过GPR75激活GQ信号。定量聚合酶链式反应和流式细胞仪检测表明，这些细胞表达GPR75，但不表达CCR5、CCR3和CCR1受体。然后用SY-SY5Y细胞检测CCL5介导的信号转导。我们报道CCL5可促进蛋白激酶B、糖原合成酶β和细胞外信号调节激酶1/2的磷酸化，并呈时间和浓度依赖性。此外，CCL5促进GPR75的时间依赖性内化。最后，通过CRISPR-Cas9方法下调GPR75的表达抑制了CCL5激活SH-SY5Y细胞中PERK的能力。因此，我们认为GPR75是一种新的CCL5受体，可以解释这种趋化因子的部分药理作用。这些发现可能有助于开发模拟CCL5的小分子GPR75激动剂。趋化因子CCL5主要与趋化因子受体CCR5结合。然而，CCL5诱导细胞外信号调节蛋白激酶(ERK)和蛋白激酶B(Akt)通路，即使在不表达CCR5的细胞中也是如此。在这份报告中，我们展示了CCL5激活G蛋白偶联受体75(GPR75)。该受体主要在神经元中表达，不属于趋化因子受体家族。我们的结果表明，GPR75是一种新的受体，可以介导CCL5对神经元的作用。
The chemokine CCL5 prevents neuronal cell death mediated both by amyloid β, as well as the human immunodeficiency virus (HIV) viral proteins gp120 and Tat. Because CCL5 binds to CCR5, CCR3 and/or CCR1 receptors, it is unclear which of these receptors plays a role in neuroprotection. Indeed, CCL5 also has neuroprotective activity in cells lacking these receptors. CCL5 may bind to a G protein-coupled receptor 75 (GPR75), which encodes for a 540 amino-acid orphan receptor of the Gqα family. In this study, we have used SH-SY5Y human neuroblastoma cells to characterize whether CCL5 could activate a Gq signaling through GPR75. Both qPCR and flow cytometry show that these cells express GPR75 but do not express CCR5, CCR3 or CCR1 receptors. SY-SY5Y cells were then used to examine CCL5-mediated signaling. We report that CCL5 promotes a time- and concentration-dependent phosphorylation of protein kinase B (AKT), glycogen synthase kinase 3β and extracellular signal–regulated kinase (ERK) 1/2. Specific antagonists of CCR5, CCR3 and CCR1 did not prevent CCL5 from increasing phosphorylated AKT or ERK. Moreover, CCL5 promotes a time-dependent internalization of GPR75. Lastly, knocking down GPR75 expression by a CRISPR-Cas9 approach inhibited the ability of CCL5 to activate pERK in SH-SY5Y cells. Therefore, we propose that GPR75 is a novel receptor for CCL5 that could explain some of the pharmacological action of this chemokine. These findings may help in the development of small molecule GPR75 agonists that mimic CCL5. The chemokine CCL5 is known to bind predominantly to chemokine receptor CCR5. However, CCL5 induces extracellular signaling-regulated kinases (Erk) and protein kinase B (Akt) pathways, even in cells that do not express CCR5. In this report we show that CCL5 activates G protein-coupled receptor 75 (GPR75). This receptor is predominantly expressed in neurons and does not belong to the chemokine receptor family. Our results suggest that GPR75 is a novel receptor that could mediate the effect of CCL5 on neurons.
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影响因子：
16.2
作者：
Civelli O
通讯作者：
Civelli O
DOI：
10.1073/pnas.96.14.8212
发表时间：
1999-07-06
影响因子：
11.1
作者：
Kaul, M;Lipton, SA
通讯作者：
Lipton, SA
影响因子：
4.8
作者：
Schecter, AD;Rollins, BJ;Taubman, MB
通讯作者：
Taubman, MB
影响因子：
7.3
作者：
Ignatov, A.;Robert, J.;Schaller, H. C.
通讯作者：
Schaller, H. C.
影响因子：
7.3
作者：
Doria JG;Silva FR;de Souza JM;Vieira LB;Carvalho TG;Reis HJ;Pereira GS;Dobransky T;Ribeiro FM
通讯作者：
Ribeiro FM