Gq activity- and β-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are required for male fertility
- Shandong University School of Medicine, China
- Duke University, United States
- Peking University, China
- Sungkyunkwan University, Republic of Korea
- Yantai Yuhuangding Hospital, China
- Shandong University, China
- East China Normal University, China
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.
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Funding
National Natural Science Foundation of China (31470789)
- Jin-Peng Sun
Funds for International cooperation and exchange of the national natural science foundation of China (31611540337)
- Ka Young Chung
- Jin-Peng Sun
National Natural Science Foundation of China (81773704)
- Jin-Peng Sun
Shandong Natural Science Fund for Distinguished Young Scholars (JQ201517)
- Jin-Peng Sun
Shandong Provincial Natural Science Foundation (ZR2014CP007)
- Dao-Lai Zhang
National Natural Science Foundation of China (31671197)
- Xiao Yu
The Program for Changjiang Scholars and Innovative Research Team in University (IRT13028)
- Xiao Yu
National Natural Science Foundation of China (31471102)
- Xiao Yu
National Science Fund for Distinguished Young Scholars (81525005)
- Fan Yi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Mice were individually housed in the Shandong university on a 12:12 light:dark cycle with access to food and water ad libitum.The use of mice was approved by the animal ethics committee of Shandong university medical school (protocol LL-201502036). All animal care and experiments were reviewed and approved by the Animal Use Committee of Shandong University School of Medicine.
Copyright
© 2018, Zhang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Gq activity- and β-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are required for male fertility
eLife 7:e33432.
https://doi.org/10.7554/eLife.33432
