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

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.

• Publication year

  2018

• Venue

  eLife

• Publication date

  2018-02-02

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.7554/eLife.33432PMID 29393851PMCID 5839696
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Homocysteine directly interacts and activates the angiotensin II type I receptor to aggravate vascular injury

  2018cited by this paper
• Adhesion G Protein-Coupled Receptors as Drug Targets.

  2018influential reference
• Arrestin-biased AT1R agonism induces acute catecholamine secretion through TRPC3 coupling

  2017influential reference
• Distinct conformations of GPCR–β-arrestin complexes mediate desensitization, signaling, and endocytosis

  2017cited by this paper
• Adaptive Activation of a Stress Response Pathway Improves Learning and Memory Through Gs and β-Arrestin-1-Regulated Lactate Metabolism.

  2017cited by this paper
• Phosphorylation of G Protein-Coupled Receptors: From the Barcode Hypothesis to the Flute Model

  2017cited by this paper
• Allosteric coupling from G protein to the agonist binding pocket in GPCRs

  2016cited by this paper
• β-Arrestin biosensors reveal a rapid, receptor-dependent activation/deactivation cycle

  2016cited by this paper
• Targeted Elimination of G Proteins and Arrestins Defines Their Specific Contributions to Both Intensity and Duration of G Protein-coupled Receptor Signaling*

  2016influential reference
• The role of G protein-coupled receptors in cochlear planar cell polarity.

  2016cited by this paper
• GPCR-G Protein-β-Arrestin Super-Complex Mediates Sustained G Protein Signaling.

  2016influential reference
• Different downstream signalling of CCK1 receptors regulates distinct functions of CCK in pancreatic beta cells

  2015cited by this paper
• The adhesion GPCR GPR126 has distinct, domain-dependent functions in Schwann cell development mediated by interaction with laminin-211.

  2015cited by this paper
• Absence of sperm RNA elements correlates with idiopathic male infertility

  2015cited by this paper
• Adhesion G Protein–Coupled Receptors: From In Vitro Pharmacology to In Vivo Mechanisms

  2015cited by this paper
• Phospho-selective mechanisms of arrestin conformations and functions revealed by unnatural amino acid incorporation and 19F-NMR

  2015cited by this paper
• The adhesion GPCR latrophilin/CIRL shapes mechanosensation.

  2015cited by this paper
• International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein–Coupled Receptors

  2015cited by this paper
• Constitutive Gαi Coupling Activity of Very Large G Protein-coupled Receptor 1 (VLGR1) and Its Regulation by PDZD7 Protein*

  2014influential reference
• Cystic fibrosis genetics: from molecular understanding to clinical application

  2014cited by this paper
• Glucose-induced electrical activities and insulin secretion in pancreatic islet β-cells are modulated by CFTR

  2014cited by this paper
• A stress response pathway in mice upregulates somatostatin level and transcription in pancreatic delta cells through Gs and β-arrestin 1

  2014cited by this paper
• Carrier screening for cystic fibrosis in the new era of medications that restore CFTR function.

  2014cited by this paper
• Loss of Slc26a9 anion transporter alters intestinal electrolyte and HCO3- transport and reduces survival in CFTR-deficient mice

  2014cited by this paper
• Loss of downregulated in adenoma (DRA) impairs mucosal HCO3− secretion in murine ileocolonic inflammation

  2012cited by this paper
• Male infertility: a critical review of pharmacologic management

  2012cited by this paper
• Regulation of male fertility by CFTR and implications in male infertility.

  2012cited by this paper
• ATP secretion in the male reproductive tract: essential role of CFTR

  2012cited by this paper
• The Very Large G Protein Coupled Receptor (Vlgr1) in Hair Cells

  2012cited by this paper
• Crystal Structure of the β2Adrenergic Receptor-Gs protein complex

  2011cited by this paper
• Voltage- and calcium-dependent gating of TMEM16A/Ano1 chloride channels are physically coupled by the first intracellular loop

  2011cited by this paper
• The N Terminus of the Adhesion G Protein-coupled Receptor GPR56 Controls Receptor Signaling Activity*

  2011cited by this paper
• Curcumin and genistein additively potentiate G551D-CFTR.

  2011cited by this paper
• Mouse cystic fibrosis transmembrane conductance regulator forms cAMP-PKA–regulated apical chloride channels in cortical collecting duct

  2010cited by this paper
• Structural Determinants of G-protein α Subunit Selectivity by Regulator of G-protein Signaling 2 (RGS2)*

  2009cited by this paper
• ADAMTS-7 Mediates Vascular Smooth Muscle Cell Migration and Neointima Formation in Balloon-Injured Rat Arteries

  2009cited by this paper
• Engineered luciferases for molecular sensing in living cells.

  2009cited by this paper
• Lentiviral gene transduction of mouse and human stem cells.

  2008cited by this paper
• Transepithelial projections from basal cells are luminal sensors in pseudostratified epithelia.

  2008cited by this paper
• Novel genetically encoded biosensors using firefly luciferase.

  2008cited by this paper
• A protocol for rapid generation of recombinant adenoviruses using the AdEasy system

  2007cited by this paper
• Defective postnatal development of the male reproductive tract in LGR4 knockout mice.

  2006cited by this paper
• New approaches for male fertility control: HE6 as an example of a putative target.

  2006cited by this paper
• An unexpected role for angiotensin II in the link between dietary salt and proximal reabsorption.

  2006cited by this paper
• Production and purification of lentiviral vectors

  2006cited by this paper
• Slc26a6 regulates CFTR activity in vivo to determine pancreatic duct HCO3− secretion: relevance to cystic fibrosis

  2006cited by this paper
• Activation of GPCRs modulates quantal size in chromaffin cells through Gβγ and PKC

  2005cited by this paper
• Activation of GPCRs modulates quantal size in chromaffin cells through G(betagamma) and PKC.

  2005cited by this paper
• Targeted Deletion of the Epididymal Receptor HE6 Results in Fluid Dysregulation and Male Infertility

  2004influential reference
• Stimulatory and inhibitory protein kinase C consensus sequences regulate the cystic fibrosis transmembrane conductance regulator

  2003cited by this paper
• Indazole Inhibition of Cystic Fibrosis Transmembrane Conductance Regulator Cl− Channels in Rat Epididymal Epithelial Cells1

  2002cited by this paper
• The Efferent Ductules: Structure and Functions

  2002cited by this paper
• Barttin is a Cl- channel β-subunit crucial for renal Cl- reabsorption and inner ear K+ secretion

  2001cited by this paper
• Defective Fluid Secretion and NaCl Absorption in the Parotid Glands of Na+/H+ Exchanger-deficient Mice*

  2001cited by this paper
• Estrogen action and male fertility: Roles of the sodium/hydrogen exchanger-3 and fluid reabsorption in reproductive tract function

  2001cited by this paper
• Expression of Multiple Na+/H+ Exchanger Isoforms in Cultured Epithelial Cells from Rat Efferent Duct and Cauda Epididymidis1

  2001cited by this paper
• Sodium-potassium-chloride cotransport.

  2000cited by this paper
• Renal proximal tubular AT2 receptor: signaling and transport.

  1999cited by this paper
• Apical proteins stimulate complement synthesis by cultured human proximal tubular epithelial cells.

  1999cited by this paper
• Testicular biopsy in patients with obstructive azoospermia.

  1999cited by this paper
• A role for oestrogens in the male reproductive system

  1997cited by this paper
• Phosphorylation by Protein Kinase C Is Required For Acute Activation of Cystic Fibrosis Transmembrane Conductance Regulator by Protein Kinase A*

  1997cited by this paper
• Physiology of V-ATPases.

  1992cited by this paper
• SNARF-1 as an intracellular pH indicator in laser microspectrofluorometry: a critical assessment.

  1991cited by this paper
• Testicular obstruction: clinicopathological studies.

  1990cited by this paper
• Cytoplasmic pH regulation and chloride/bicarbonate exchange in avian osteoclasts.

  1989cited by this paper
• Expression of Multiple Na/H Exchanger Isoforms in Cultured Epithelial Cells from Rat Efferent Duct and Cauda Epididymidis1

  year unknowncited by this paper

• Adhesion G protein-coupled receptors

  2026cites this paper
• Dehydroepiandrosterone activates ADGRG2 to regulate chloride homeostasis and sperm motility via Gs-cAMP pathways.

  2026cites this paper
• Clinical subgroup-stratified plasma proteomic signatures improve risk prediction for myocardial infarction: SCORE2-Pro

  2026cites this paper
• GPR146 Facilitates Blood Pressure Elevation and Vascular Remodeling via PIEZO1.

  2025cites this paper
• Cryo-EM structural elucidation and molecular mechanism of the GPR133-G13 signaling complex.

  2025cites this paper
• The structural basis of the G protein–coupled receptor and ion channel axis

  2025cites this paper
• Development of an allosteric adhesion GPCR nanobody with therapeutic potential

  2025influential citation
• Identification of antimalarial drugs and bradykinin as ligands of the Plasmodium membrane protein PfSR10

  2025cites this paper
• Adhesion Class GPCRs in GtoPdb v.2025.3

  2025cites this paper
• New insights into sperm physiology regulation: Enlightenment from G‐protein‐coupled receptors

  2024cites this paper
• Targeting adhesion G protein-coupled receptors. Current status and future perspectives.

  2024cites this paper
• ARL13B controls male reproductive tract physiology through primary and Motile Cilia

  2024influential citation
• Sensing steroid hormone 17α-hydroxypregnenolone by GPR56 enables protection from ferroptosis-induced liver injury.

  2024cites this paper
• Establishment of tumor microenvironment following bisphenol A exposure in the testis.

  2024cites this paper
• Differential contributions of G protein‐ or arrestin subtype‐mediated signalling underlie urocortin 3‐induced somatostatin secretion in pancreatic δ cells

  2024cites this paper
• SperMD: the expression atlas of sperm maturation

  2024cites this paper
• Conformational transitions and activation of the adhesion receptor CD97.

  2024cites this paper
• Adhesion G protein-coupled receptors-Structure and functions.

  2023cites this paper
• Mechanistic Insights into Peptide Binding and Deactivation of an Adhesion G Protein-Coupled Receptor

  2023cites this paper
• Structure of GPR101–Gs enables identification of ligands with rejuvenating potential

  2023influential citation
• Proteomic approach towards identification of seminal fluid biomarkers from individuals with severe oligozoospermia, cryptozoospermia and non-obstructive azoospermia: a pilot study

  2023cites this paper
• Functional screening and rational design of compounds targeting GPR132 to treat diabetes

  2023cites this paper
• Structure-function of DHEA binding proteins.

  2023cites this paper
• GPR114/ADGRG5 is activated by its tethered peptide agonist because it is a cleaved adhesion GPCR

  2023cites this paper
• Eif2s3y alleviated LPS-induced damage to mouse testis and maintained spermatogenesis by negatively regulating Adamts5.

  2023cites this paper
• Adhesion G protein-coupled receptor G2 is dispensable for lumicrine signaling regulating epididymal initial segment differentiation and gene expression

  2023cites this paper
• Tissue-Specific Regulation of CFTR Gene Expression

  2023cites this paper
• A novel ADGRG2 truncating variant associated with X-linked obstructive azoospermia in a large Chinese pedigree

  2023influential citation
• Adhesion Class GPCRs in GtoPdb v.2023.1 Adhesion Class GPCRs in GtoPdb v.2023.1

  2023cites this paper
• Deafness‐Associated ADGRV1 Mutation Impairs USH2A Stability through Improper Phosphorylation of WHRN and WDSUB1 Recruitment

  2023cites this paper
• Deleterious variants in TAF7L cause human oligoasthenoteratozoospermia and its impairing histone to protamine exchange inducing reduced in vitro fertilization

  2023cites this paper
• Structure insights into selective coupling of G protein subtypes by a class B G protein-coupled receptor

  2022cites this paper
• Autonomous sensing of the insulin peptide by an olfactory G protein-coupled receptor modulates glucose metabolism.

  2022cites this paper
• A molecular mechanism of UDCA engagement with GPBAR and subsequent G protein interaction revealed by scattered alanine scanning.

  2022cites this paper
• Progesterone activates GPR126 to promote breast cancer development via the Gi pathway

  2022cites this paper
• A correlation study of adhesion G protein-coupled receptors as potential therapeutic targets in Uterine Corpus Endometrial cancer.

  2022cites this paper
• Structural basis for the tethered peptide activation of adhesion GPCRs

  2022cites this paper
• Tethered peptide activation mechanism of the adhesion GPCRs ADGRG2 and ADGRG4

  2022cites this paper
• Adhesion G Protein-Coupled Receptors: Structure, Signaling, Physiology and Pathophysiology.

  2022influential citation
• Endogenous Lipid-GPR120 Signaling Modulates Pancreatic Islet Homeostasis to Different Extents.

  2022cites this paper
• Structures of the ADGRG2–Gs complex in apo and ligand-bound forms

  2022cites this paper
• Gq Signaling in Autophagy Control: Between Chemical and Mechanical Cues

  2022cites this paper
• G-Protein Coupled Receptors in Human Sperm: An In Silico Approach to Identify Potential Modulatory Targets

  2022cites this paper
• An ionic lock and a hydrophobic zipper mediate the coupling between an insect pheromone receptor BmOR3 and downstream effectors

  2021cites this paper
• Emerging roles of adhesion G protein-coupled receptors

  2021cites this paper
• Single-molecule FRET and conformational analysis of beta-arrestin-1 through genetic code expansion and a Se-click reaction†

  2021cites this paper
• Adhesion Class GPCRs in GtoPdb v.2021.3

  2021cites this paper
• Expression Profile of New Marker Genes Involved in Differentiation of Canine Adipose-Derived Stem Cells into Osteoblasts

  2021cites this paper
• Clinical and Functional Characteristics of a Novel KLF11 Cys354Phe Variant Involved in Maturity-Onset Diabetes of the Young

  2021cites this paper
• Receptor-Arrestin Interactions: The GPCR Perspective

  2021cites this paper
• Dissecting the structural features of β-arrestins as multifunctional proteins.

  2021cites this paper
• Structures of the glucocorticoid-bound adhesion receptor GPR97–Go complex

  2021cites this paper
• Transcriptomic and metabolomic insights into the variety of sperm storage in oviduct of egg layers

  2021cites this paper
• Activation of PTH1R alleviates epididymitis and orchitis through Gq and β-arrestin-1 pathways

  2021cites this paper
• A guide to adhesion GPCR research

  2021cites this paper
• Conserved residues in the extracellular loop 2 regulate Stachel-mediated activation of ADGRG2

  2021cites this paper
• Biased GPCR signaling: Possible mechanisms and inherent limitations.

  2020cites this paper
• Genetics of the congenital absence of the vas deferens

  2020cites this paper
• Cell active and functionally-relevant small-molecule agonists of calcitonin receptor.

  2020cites this paper
• The Emerging Role of Adhesion GPCRs in Cancer.

  2020cites this paper
• Structure, function and therapeutic potential of adhesion GPCRs

  2020cites this paper
• Adhesion G protein-coupled receptors-Candidate metabotropic mechanosensors and novel drug targets.

  2020cites this paper
• Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as targets for allosteric drug design

  2020cites this paper
• Congenital absence of the vas deferens: Cystic fibrosis transmembrane regulatory gene mutations.

  2020cites this paper
• Optimization of a peptide ligand for the adhesion GPCR ADGRG2 provides a potent tool to explore receptor biology

  2020influential citation
• Function and therapeutic potential of GPCRs in epididymis

  2020cites this paper
• DeSiphering receptor core-induced and ligand-dependent conformational changes in arrestin via genetic encoded trimethylsilyl 1H-NMR probe

  2020cites this paper
• Function and therapeutic potential of G protein‐coupled receptors in epididymis

  2020cites this paper
• G12/13 is activated by acute tethered agonist exposure in the adhesion GPCR ADGRL3

  2020cites this paper
• Seminal Plasma Proteome as an Indicator of Sperm Dysfunction and Low Sperm Motility in Chickens

  2020cites this paper
• A novel hemizygous loss-of-function mutation in ADGRG2 causes male infertility with congenital bilateral absence of the vas deferens

  2020influential citation
• Adhesion GPCRs as a paradigm for understanding polycystin-1 G protein regulation.

  2020cites this paper
• PTP-MEG2 regulates quantal size and fusion pore opening through two distinct structural bases and substrates

  2019cites this paper
• Genetische Heterogenität der angeborenen Samenleiteraplasie // Genetic Heterogeneity of Congenital Vas Deferens Aplasia

  2019cites this paper
• Arrestin‐independent constitutive endocytosis of GPR125/ADGRA3

  2019cites this paper
• Novel ADGRG2 truncating variants in patients with X‐linked congenital absence of vas deferens

  2019cites this paper
• The X chromosome and male infertility

  2019cites this paper
• Genetic defects in human azoospermia

  2019cites this paper
• Deletion of pancreatic β‐cell adenosine kinase improves glucose homeostasis in young mice and ameliorates streptozotocin‐induced hyperglycaemia

  2019cites this paper
• Structural Mechanism of the Arrestin-3/JNK3 Interaction.

  2019cites this paper
• Adhesion G protein-coupled receptors: opportunities for drug discovery

  2019cites this paper
• Spatial regulation of GPR64/ADGRG2 signaling by β‐arrestins and GPCR kinases

  2019cites this paper
• Genetische Heterogenität der angeborenen Samenleiteraplasie // Genetic Heterogeneity of Congenital Vas Deferens Aplasia

  2018cites this paper
• Structural studies and drug discovery of G protein-coupled receptors

  2018cites this paper