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Elife. 2018 Feb 2;7. pii: e33432. doi: 10.7554/eLife.33432.

Gq activity- and β-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are required for male fertility.

Zhang DL#1,2,3, Sun YJ#1,2, Ma ML#1,2, Wang YJ#1,2, Lin H1,2, Li RR1,2, Liang ZL1,2, Gao Y1,2, Yang Z1,2, He DF1,2, Lin A4, Mo H1,2, Lu YJ1,2, Li MJ1,2, Kong W5, Chung KY6, Yi F7, Li JY8, Qin YY9, Li J2, Thomsen ARB4, Kahsai AW4, Chen ZJ9, Xu ZG10, Liu M11,12, Li D11, Yu X2, Sun JP1,4.

Author information

1
Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China.
2
Department of Physiology, Shandong University School of Medicine, Jinan, China.
3
School of Pharmacy, Binzhou Medical University, Yantai, China.
4
Department of Biochemistry, School of Medicine, Duke University, Durham, United States.
5
Key Laboratory of Molecular Cardiovascular Science, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China.
6
School of Pharmacy, Sungkyunkwan University, Suwon, Korea.
7
Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
8
Key Laboratory of Male Reproductive Health, National Research Institute for Family Planning, National Health and Family Planning Commission, Beijing, China.
9
National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China.
10
Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, Shandong University School of Life Sciences, Jinan, China.
11
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, Institute of Biomedical Sciences, East China Normal University, Shanghai, China.
12
Department of Molecular and Cellular Medicine, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, United States.
#
Contributed equally

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.

KEYWORDS:

ADGRG2; CFTR; G protein; GPCR; arrestin; biochemistry; chemical biology; infertility; mouse

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