Robichaux William G, Branham-O'Connor Melissa, Hwang Il-Young, Vural Ali, Kehrl Johne H, Blumer Joe B
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina (W.G.R., M.B.-O., J.B.B.); and B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (I.-Y.H., A.V., J.H.K.).
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina (W.G.R., M.B.-O., J.B.B.); and B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (I.-Y.H., A.V., J.H.K.)
J Pharmacol Exp Ther. 2017 Mar;360(3):424-433. doi: 10.1124/jpet.116.238436. Epub 2017 Jan 6.
Activator of G-protein signaling 4 (AGS4)/G-protein signaling modulator 3 (Gpsm3) contains three G-protein regulatory (GPR) motifs, each of which can bind Gi-GDP free of G We previously demonstrated that the AGS4-Gi interaction is regulated by seven transmembrane-spanning receptors (7-TMR), which may reflect direct coupling of the GPR-Gi module to the receptor analogous to canonical G heterotrimer. We have demonstrated that the AGS4-Gi complex is regulated by chemokine receptors in an agonist-dependent manner that is receptor-proximal. As an initial approach to investigate the functional role(s) of this regulated interaction in vivo, we analyzed leukocytes, in which AGS4/Gpsm3 is predominantly expressed, from AGS4/Gpsm3-null mice. Loss of AGS4/Gpsm3 resulted in mild but significant neutropenia and leukocytosis. Dendritic cells, T lymphocytes, and neutrophils from AGS4/Gpsm3-null mice also exhibited significant defects in chemoattractant-directed chemotaxis and extracellular signal-regulated kinase activation. An in vivo peritonitis model revealed a dramatic reduction in the ability of AGS4/Gpsm3-null neutrophils to migrate to primary sites of inflammation. Taken together, these data suggest that AGS4/Gpsm3 is required for proper chemokine signal processing in leukocytes and provide further evidence for the importance of the GPR-Gi module in the regulation of leukocyte function.
G蛋白信号激活因子4（AGS4）/G蛋白信号调节剂3（Gpsm3）包含三个G蛋白调节（GPR）基序，每个基序都能结合游离的Gi-GDP而不结合G。我们之前证明，AGS4与Gi的相互作用受七次跨膜受体（7-TMR）调节，这可能反映了GPR-Gi模块与受体的直接偶联，类似于经典的G异源三聚体。我们已经证明，AGS4-Gi复合物受趋化因子受体以受体近端的激动剂依赖性方式调节。作为研究这种调节相互作用在体内功能作用的初步方法，我们分析了AGS4/Gpsm3基因敲除小鼠中主要表达AGS4/Gpsm3的白细胞。AGS4/Gpsm3的缺失导致轻度但显著的中性粒细胞减少和白细胞增多。AGS4/Gpsm3基因敲除小鼠的树突状细胞、T淋巴细胞和中性粒细胞在趋化因子导向的趋化作用和细胞外信号调节激酶激活方面也表现出显著缺陷。体内腹膜炎模型显示，AGS4/Gpsm3基因敲除的中性粒细胞迁移到炎症原发部位的能力显著降低。综上所述，这些数据表明AGS4/Gpsm3是白细胞中趋化因子信号正常处理所必需的，并为GPR-Gi模块在调节白细胞功能中的重要性提供了进一步证据。
