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

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Zhang, D-L; Sun, Y-J; Ma, M-L; Wang, Y-J; Lin, H; Li, R-R; Liang, Z-L; Gao, Y; Yang, Z; He, D-F; Lin, A; Mo, H; Lu, Y-J; Li, M-J; Kong, W; Chung, KY; Yi, F; Li, J-Y; Qin, Y-Y; Li, J; Thomsen, ARB; Kahsai, AW; Chen, Z-J; Xu, Z-G; Liu, M; Li, D; Yu, X; Sun, J-P

Published Date

  • February 2, 2018

Published In

Volume / Issue

  • 7 /

PubMed ID

  • 29393851

Pubmed Central ID

  • 29393851

Electronic International Standard Serial Number (EISSN)

  • 2050-084X

Digital Object Identifier (DOI)

  • 10.7554/eLife.33432

Language

  • eng

Conference Location

  • England