1. Gq activity- and β-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are required for male fertility
- Author
-
Dao Lai Zhang, Rui Rui Li, Zong Lai Liang, Alem W. Kahsai, Alex R.B. Thomsen, Yuan Gao, Dali Li, Yu Jing Lu, Fan Yi, Ying Ying Qin, Ka Young Chung, Hui Mo, Amy Lin, Hui Lin, Jian Yuan Li, Yi Jing Wang, Ming-Liang Ma, Zhigang Xu, Yu Jing Sun, Zhao Yang, Jin-Peng Sun, Wei Kong, Jingxin Li, Xiao Yu, Dong Fang He, Zi-Jiang Chen, Meng Jing Li, and Mingyao Liu
- Subjects
0301 basic medicine ,Male ,ADGRG2 ,Mouse ,QH301-705.5 ,G protein ,Science ,Efferent ,Cystic Fibrosis Transmembrane Conductance Regulator ,General Biochemistry, Genetics and Molecular Biology ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,GPCR ,Biochemistry and Chemical Biology ,Arrestin ,Animals ,Biology (General) ,CFTR ,Ion channel ,G protein-coupled receptor ,Orphan receptor ,Mice, Knockout ,General Immunology and Microbiology ,Chemistry ,Reabsorption ,arrestin ,General Neuroscience ,General Medicine ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,Fertility ,beta-Arrestin 1 ,Medicine ,GTP-Binding Protein alpha Subunits, Gq-G11 ,infertility ,Homeostasis ,Research Article - 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.
- Published
- 2017