Dominant-negative Gα subunits are a mechanism of dysregulated heterotrimeric G protein signaling in human disease.
Sci Signal
; 9(423): ra37, 2016 Apr 12.
Article
en En
| MEDLINE
| ID: mdl-27072656
ABSTRACT
Auriculo-condylar syndrome (ACS), a rare condition that impairs craniofacial development, is caused by mutations in a G protein-coupled receptor (GPCR) signaling pathway. In mice, disruption of signaling by the endothelin type A receptor (ET(A)R), which is mediated by the G protein (heterotrimeric guanine nucleotide-binding protein) subunit Gα(q/11) and subsequently phospholipase C (PLC), impairs neural crest cell differentiation that is required for normal craniofacial development. Some ACS patients have mutations inGNAI3, which encodes Gα(i3), but it is unknown whether this G protein has a role within the ET(A)R pathway. We used a Xenopus model of vertebrate development, in vitro biochemistry, and biosensors of G protein activity in mammalian cells to systematically characterize the phenotype and function of all known ACS-associated Gα(i3) mutants. We found that ACS-associated mutations in GNAI3 produce dominant-negative Gα(i3) mutant proteins that couple to ET(A)R but cannot bind and hydrolyze guanosine triphosphate, resulting in the prevention of endothelin-mediated activation of Gα(q/11) and PLC. Thus, ACS is caused by functionally dominant-negative mutations in a heterotrimeric G protein subunit.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Transducción de Señal
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Subunidades alfa de la Proteína de Unión al GTP Gi-Go
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Oído
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Enfermedades del Oído
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Mutación
Límite:
Animals
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Humans
Idioma:
En
Revista:
Sci Signal
Asunto de la revista:
CIENCIA
/
FISIOLOGIA
Año:
2016
Tipo del documento:
Article
País de afiliación:
Estados Unidos