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

eLife | Feb 2, 2018

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.

Pubmed ID: 29393851 RIS Download

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Associated grants

  • Agency: National Natural Science Foundation of China, Id: 31470789
  • Agency: National Natural Science Foundation of China, Id: 31611540337
  • Agency: National Natural Science Foundation of China, Id: 81773704
  • Agency: Shandong Natural Science Fund for Distinguished Young Scholars, Id: JQ201517
  • Agency: Shandong Provincial Natural Science Foundation, Id: ZR2014CP007
  • Agency: National Natural Science Foundation of China, Id: 31671197
  • Agency: The Program for Changjiang Scholars and Innovative Research Team in University, Id: IRT13028
  • Agency: National Natural Science Foundation of China, Id: 31471102
  • Agency: National Science Fund for Distinguished Young Scholars, Id: 81525005
  • Agency: Funds for International cooperation and exchange of the national natural science foundation of China, Id: 31611540337

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