eLife
·
2018
·
IF 7.616
Dao-Lai Zhang,Yu-Jing Sun,Ming-Liang Ma,Yi-jing Wang,Hui Lin,Rui-Rui Li,Zong-Lai Liang,Yuan Gao,Zhao Yang,Dong-Fang He,Amy Lin,Hui Mo,Yu-Jing Lu,Meng-Jing Li,Wei Kong,Ka Young Chung,Fan Yi,Jian-Yuan Li,Ying-Ying Qin,Jingxin Li,Alex R B Thomsen,Alem W Kahsai,Zi-Jiang Chen,Zhi-Gang Xu,Mingyao Liu,Dali Li,Xiao Yu,Jin-Peng Sun
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.
研究领域:
分子生物学
·
生殖生物学
·
药理学
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产品关联
DOI
PubMed
高影响因子
Nature Chemical Biology
·
2022
·Vol. 18
·期 11
·1196-1203
·
IF 16.174
Lin Hui,Xiao Peng,Bu Rui-Qian,Guo Shengchao,Yang Zhao,Yuan Daopeng,Zhu Zhong-Liang,Zhang Chuan-Xin,He Qing-Tao,Zhang Chao,Ping Yu-Qi,Zhao Ru-Jia,Ma Chuan-Shun,Liu Chang-Hao,Zhang Xiao-Ning,Jiang Dan,Huang Shaohui,Xi Yue-Tong,Zhang Dao-Lai,Xue Chen-Yang,Yang Bai-Sheng,Li Jian-Yuan,Lin Hao-Cheng,Zeng Xu-Hui,Zhao Han,Xu Wen-Ming,Yi Fan,Liu Zhongmin,Sun Jin-Peng,Yu Xiao
Adhesion G protein-coupled receptors are elusive in terms of their structural information and ligands. Here, we solved the cryogenic-electron microscopy (cryo-EM) structure of apo-ADGRG2, an essential membrane receptor for maintaining male fertility, in complex with a G s trimer. Whereas the formations of two kinks were determinants of the active state, identification of a potential ligand-binding pocket in ADGRG2 facilitated the screening and identification of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate and deoxycorticosterone as potential ligands of ADGRG2. The cryo-EM structures of DHEA–ADGRG2–G s provided interaction details for DHEA within the seven transmembrane domains of ADGRG2. Collectively, our data provide a structural basis for the activation and signaling of ADGRG2, as well as characterization of steroid hormones as ADGRG2 ligands, which might be used as useful tools for further functional studies of the orphan ADGRG2.
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DOI
PubMed
高影响因子
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