Epithelial Gpr116 regulates pulmonary alveolar homeostasis via Gq/11 signaling
Epithelial Gpr116 regulates pulmonary alveolar homeostasis via Gq/11 signaling
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DOI：
10.1172/jci.insight.93700
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发表时间：
2017-06-02
期刊：
影响因子：
8
通讯作者：
Bridges, James P.
中科院分区：
文献类型：
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作者：
Brown, Kari;Filuta, Alyssa;Bridges, James P.
肺功能依赖于肺泡表面活性物质的精确调节。肺表面活性物质浓度或功能的改变损害了通气性并导致组织损伤。识别感知和调节内源性肺泡表面活性物质浓度的分子途径，以及从药物上积极和消极地调节它们的能力，将是由表面活性物质稳态破坏引起的急、慢性肺部疾病患者的主要治疗进展。孤儿黏附GPCRGPR116(也称为Adgrf5)是肺泡表面活性物质浓度的关键调节因子。在这里，我们证明了人和鼠的GPR116通过调节鸟嘌呤核苷酸结合域αQ和11(G(Q/11))信号来控制肺泡II型(AT2)细胞表面活性物质的分泌和再摄取。来自GPR116胞外区的合成肽激活依赖G(Q/11)的肌醇磷酸转化、钙动员和皮质F-肌动蛋白稳定以抑制表面活性物质的分泌。在Gpr116(-/-)小鼠中观察到的AT2细胞特异性的GNAQ和GNA11的缺失导致了表面活性物质的积累。这些数据提供了GPR116是调节内源性肺泡表面活性物质池来治疗与表面活性物质功能障碍相关的肺部疾病的合理治疗靶点的概念证据。
Pulmonary function is dependent upon the precise regulation of alveolar surfactant. Alterations in pulmonary surfactant concentrations or function impair ventilation and cause tissue injury. Identification of the molecular pathways that sense and regulate endogenous alveolar surfactant concentrations, coupled with the ability to pharmacologically modulate them both positively and negatively, would be a major therapeutic advance for patients with acute and chronic lung diseases caused by disruption of surfactant homeostasis. The orphan adhesion GPCR GPR116 (also known as Adgrf5) is a critical regulator of alveolar surfactant concentrations. Here, we show that human and mouse GPR116 control surfactant secretion and reuptake in alveolar type II (AT2) cells by regulating guanine nucleotide-binding domain alpha q and 11 (G(q/11)) signaling. Synthetic peptides derived from the ectodomain of GPR116 activated G(q/11)-dependent inositol phosphate conversion, calcium mobilization, and cortical F-actin stabilization to inhibit surfactant secretion. AT2 cell-specific deletion of Gnaq and Gna11 phenocopied the accumulation of surfactant observed in Gpr116(-/-) mice. These data provide proof of concept that GPR116 is a plausible therapeutic target to modulate endogenous alveolar surfactant pools to treat pulmonary diseases associated with surfactant dysfunction.