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

  1. Dao-Lai Zhang
  2. Yu-Jing Sun
  3. Ming-Liang Ma
  4. Yi-jing Wang
  5. Hui Lin
  6. Rui-Rui Li
  7. Zong-Lai Liang
  8. Yuan Gao
  9. Zhao Yang
  10. Dong-Fang He
  11. Amy Lin
  12. Hui Mo
  13. Yu-Jing Lu
  14. Meng-Jing Li
  15. Wei Kong
  16. Ka Young Chung
  17. Fan Yi
  18. Jian-Yuan Li
  19. Ying-Ying Qin
  20. Jingxin Li
  21. Alex R B Thomsen
  22. Alem W Kahsai
  23. Zi-Jiang Chen
  24. Zhi-Gang Xu
  25. Mingyao Liu
  26. Dali Li  Is a corresponding author
  27. Xiao Yu  Is a corresponding author
  28. Jin-Peng Sun  Is a corresponding author
  1. Shandong University School of Medicine, China
  2. Duke University, United States
  3. Peking University, China
  4. Sungkyunkwan University, Republic of Korea
  5. Yantai Yuhuangding Hospital, China
  6. Shandong University, China
  7. 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.

Article and author information

Author details

  1. Dao-Lai Zhang

    Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Yu-Jing Sun

    Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Ming-Liang Ma

    Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Yi-jing Wang

    Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Hui Lin

    Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Rui-Rui Li

    Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Zong-Lai Liang

    Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Yuan Gao

    Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Zhao Yang

    Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Dong-Fang He

    Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Amy Lin

    Department of Biochemistry, Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6723-5443
  12. Hui Mo

    Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Yu-Jing Lu

    Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Meng-Jing Li

    Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China
    Competing interests
    The authors declare that no competing interests exist.
  15. Wei Kong

    Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  16. Ka Young Chung

    School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  17. Fan Yi

    Department of Pharmacology, Shandong University School of Medicine, Jinan, China
    Competing interests
    The authors declare that no competing interests exist.
  18. Jian-Yuan Li

    Shandong Stem Cell Engineering Technology Research Center, Yantai Yuhuangding Hospital, Yantai, China
    Competing interests
    The authors declare that no competing interests exist.
  19. Ying-Ying Qin

    National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
    Competing interests
    The authors declare that no competing interests exist.
  20. Jingxin Li

    Department of Physiology, Shandong University School of Medicine, Jinan, China
    Competing interests
    The authors declare that no competing interests exist.
  21. Alex R B Thomsen

    Department of Biochemistry, Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  22. Alem W Kahsai

    Department of Biochemistry, Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  23. Zi-Jiang Chen

    National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
    Competing interests
    The authors declare that no competing interests exist.
  24. Zhi-Gang Xu

    Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan, China
    Competing interests
    The authors declare that no competing interests exist.
  25. Mingyao Liu

    Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  26. Dali Li

    Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
    For correspondence
    dlli@bio.ecnu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  27. Xiao Yu

    Department of Physiology, Shandong University School of Medicine, Jinan, China
    For correspondence
    yuxiao@sdu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  28. Jin-Peng Sun

    Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China
    For correspondence
    sunjinpeng@sdu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3572-1580

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.

Reviewing Editor

  1. Michel Bagnat, Duke University, United States

Publication history

  1. Received: November 8, 2017
  2. Accepted: January 30, 2018
  3. Accepted Manuscript published: February 2, 2018 (version 1)
  4. Version of Record published: March 6, 2018 (version 2)

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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  1. Dao-Lai Zhang
  2. Yu-Jing Sun
  3. Ming-Liang Ma
  4. Yi-jing Wang
  5. Hui Lin
  6. Rui-Rui Li
  7. Zong-Lai Liang
  8. Yuan Gao
  9. Zhao Yang
  10. Dong-Fang He
  11. Amy Lin
  12. Hui Mo
  13. Yu-Jing Lu
  14. Meng-Jing Li
  15. Wei Kong
  16. Ka Young Chung
  17. Fan Yi
  18. Jian-Yuan Li
  19. Ying-Ying Qin
  20. Jingxin Li
  21. Alex R B Thomsen
  22. Alem W Kahsai
  23. Zi-Jiang Chen
  24. Zhi-Gang Xu
  25. Mingyao Liu
  26. Dali Li
  27. Xiao Yu
  28. Jin-Peng Sun
(2018)
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

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