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Abstract：
Luminal fluid reabsorption plays a fundamental role in male fertility. We demonstrated that the ubiquitous GPCR signaling proteins Gq and β-arrestin-1 are essential for fluid reabsorption because they mediate coupling between an orphan receptor ADGRG2 (GPR64) and the ion channel CFTR. A reduction in protein level or deficiency of ADGRG2, Gq or β-arrestin-1 in a mouse model led to an imbalance in pH homeostasis in the efferent ductules due to decreased constitutive CFTR currents. Efferent ductule dysfunction was rescued by the specific activation of another GPCR, AGTR2. Further mechanistic analysis revealed that β-arrestin-1 acts as a scaffold for ADGRG2/CFTR complex formation in apical membranes, whereas specific residues of ADGRG2 confer coupling specificity for different G protein subtypes, this specificity is critical for male fertility. Therefore, manipulation of the signaling components of the ADGRG2-Gq/β-arrestin-1/CFTR complex by small molecules may be an effective therapeutic strategy for male infertility.
摘要：
腔液重吸收在男性生育能力中起着基本作用。我们证明了普遍存在的GPCR信号蛋白Gq和β-arrestin-1对于液体重吸收至关重要，因为它们介导了孤儿受体ADGRG2（GPR64）与离子通道CFTR之间的偶联。小鼠模型中蛋白质水平的降低或ADGRG2，Gq或β-抑制蛋白-1的缺乏导致由于组成型CFTR电流的降低，传出小管内pH稳态的失衡。通过另一种GPCR的特异性激活来挽救传出神经导管功能障碍，AGTR2.进一步的机制分析显示，β-抑制蛋白-1作为一个支架的ADGRG2/CFTR复合物在根尖膜形成，而ADGRG2的特定残基赋予不同G蛋白亚型的偶联特异性，这种特异性对男性生育能力至关重要。因此,通过小分子操纵ADGRG2-Gq/β-抑制蛋白-1/CFTR复合物的信号成分可能是男性不育的有效治疗策略。
