Department of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178, USA.
J Allergy Clin Immunol. 2012 Oct;130(4):968-76.e3. doi: 10.1016/j.jaci.2012.05.004. Epub 2012 Jun 15.
Drugs targeting individual G protein-coupled receptors are used as asthma therapies, but this strategy is limited because of G protein-coupled receptor signal redundancy. Regulator of G protein signaling 2 (RGS2), an intracellular selective inhibitor of multiple bronchoconstrictor receptors, may play a central role in the pathophysiology and treatment of asthma.
We defined functions and mechanisms of RGS2 in regulating airway hyperresponsiveness (AHR), the pathophysiologic hallmark of asthma.
Real-time PCR and Western blot were used to determine changes in RGS2 expression in ovalbumin-sensitized/-challenged mice. We also used immunohistochemistry and real-time PCR to compare RGS2 expression between human asthmatic and control subjects. The AHR of RGS2 knockout mice was assessed by using invasive tracheostomy and unrestrained plethysmography. Effects of loss of RGS2 on mouse airway smooth muscle (ASM) remodeling, contraction, intracellular Ca(2+), and mitogenic signaling were determined in vivo and in vitro.
RGS2 was highly expressed in human and murine bronchial epithelium and ASM and was markedly downregulated in lungs of ovalbumin-sensitized/-challenged mice. Lung tissues and blood monocytes from asthma patients expressed significantly lower RGS2 protein (lung) and mRNA (monocytes) than from nonasthma subjects. The extent of reduction of RGS2 on human monocytes correlated with increased AHR. RGS2 knockout caused spontaneous AHR in mice. Loss of RGS2 augmented Ca(2+) mobilization and contraction of ASM cells. Loss of RGS2 also increased ASM mass and stimulated ASM cell growth via extracellular signal-regulated kinase and phosphatidylinositol 3-kinase pathways.
We identified RGS2 as a potent modulator of AHR and a potential novel therapeutic target for asthma.
靶向单个 G 蛋白偶联受体的药物被用作哮喘治疗药物，但由于 G 蛋白偶联受体信号冗余，这种策略受到限制。G 蛋白信号转导调节因子 2（RGS2）是多种支气管收缩受体的细胞内选择性抑制剂，可能在哮喘的病理生理学和治疗中发挥核心作用。
我们定义了 RGS2 在调节气道高反应性（AHR）中的功能和机制，AHR 是哮喘的病理生理标志。
实时 PCR 和 Western blot 用于确定卵清蛋白致敏/攻击小鼠中 RGS2 表达的变化。我们还使用免疫组织化学和实时 PCR 比较了哮喘患者和对照者之间的 RGS2 表达。通过使用有创气管切开术和非束缚式 plethysmography 评估 RGS2 敲除小鼠的 AHR。在体内和体外确定 RGS2 缺失对小鼠气道平滑肌（ASM）重塑、收缩、细胞内 Ca(2+)和有丝分裂信号的影响。
RGS2 在人支气管上皮细胞和 ASM 中高度表达，在卵清蛋白致敏/攻击的小鼠肺部明显下调。哮喘患者的肺组织和血单核细胞表达的 RGS2 蛋白（肺）和 mRNA（单核细胞）明显低于非哮喘患者。人单核细胞中 RGS2 减少的程度与 AHR 增加相关。RGS2 敲除导致小鼠自发性 AHR。RGS2 缺失增强了 ASM 细胞的 Ca(2+)动员和收缩。RGS2 缺失还通过细胞外信号调节激酶和磷脂酰肌醇 3-激酶途径增加 ASM 质量并刺激 ASM 细胞生长。
我们将 RGS2 鉴定为 AHR 的有效调节剂和哮喘的潜在新型治疗靶点。
