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

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 LiAlex R.B. Thomsen, Alem W. Kahsai, Zi Jiang Chen, Zhi Gang Xu, Mingyao Liu, Dali Li, Xiao Yu, Jin Peng Sun

Research output: Contribution to journalArticlepeer-review

Abstract

Luminal fluid reabsorption plays a fundamental role in male fertility. We demonstrated that the ubiquitous GPCR signaling proteins Gq and b-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.

Original languageEnglish (US)
Article numbere33432
JournaleLife
Volume7
DOIs
StatePublished - Feb 2 2018

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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