标题：Gq activity- and beta-arrestin-1 scaffolding mediated ADGRG2/CFTR coupling are required for male fertility
作者：Zhang, Dao-Lai; Sun, Yu-Jing; Ma, Ming-Liang; Wang, Yi-Jing; Lin, Hui; Li, Rui-Rui; Liang, Zong-Lai; Gao, Yuan; Yang, Zhao; He, Dong 更多 作者机构：[Zhang, Dao-Lai; Sun, Yu-Jing; Ma, Ming-Liang; Wang, Yi-Jing; Lin, Hui; Li, Rui-Rui; Liang, Zong-Lai; Gao, Yuan; Yang, Zhao; He, Dong-Fang; Mo, Hui; L 更多
通讯作者：Sun, JP;Yu, X;Sun, JP;Li, DL
通讯作者地址：[Sun, JP]Shandong Univ, Sch Med, Dept Biochem & Mol Biol, Key Lab Expt Teratol,Minist Educ, Jinan, Shandong, Peoples R China;[Yu, X]Shandong Univ, Sch 更多
摘要：Luminal fluid reabsorption plays a fundamental role in male fertility. We demonstrated that the ubiquitous GPCR signaling proteins Gq and beta-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 beta-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 beta-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/beta-arrestin-1/CFTR complex by small molecules may be an effective therapeutic strategy for male infertility.