Gq activity- and ß-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are required for male fertility.
Elife
; 72018 02 02.
Article
em En
| MEDLINE
| ID: mdl-29393851
ABSTRACT
Luminal fluid reabsorption plays a fundamental role in male fertility. We demonstrated that the ubiquitous GPCR signaling proteins Gq and ß-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 ß-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 ß-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/ß-arrestin-1/CFTR complex by small molecules may be an effective therapeutic strategy for male infertility.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Regulador de Condutância Transmembrana em Fibrose Cística
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Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP
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Receptores Acoplados a Proteínas G
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Fertilidade
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Beta-Arrestina 1
Limite:
Animals
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article