Cross-communication between Gi and Gs in a G-protein-coupled receptor heterotetramer guided by a receptor C-terminal domain.
BMC Biol
; 16(1): 24, 2018 02 28.
Article
em En
| MEDLINE
| ID: mdl-29486745
ABSTRACT
BACKGROUND:
G-protein-coupled receptor (GPCR) heteromeric complexes have distinct properties from homomeric GPCRs, giving rise to new receptor functionalities. Adenosine receptors (A1R or A2AR) can form A1R-A2AR heteromers (A1-A2AHet), and their activation leads to canonical G-protein-dependent (adenylate cyclase mediated) and -independent (ß-arrestin mediated) signaling. Adenosine has different affinities for A1R and A2AR, allowing the heteromeric receptor to detect its concentration by integrating the downstream Gi- and Gs-dependent signals. cAMP accumulation and ß-arrestin recruitment assays have shown that, within the complex, activation of A2AR impedes signaling via A1R.RESULTS:
We examined the mechanism by which A1-A2AHet integrates Gi- and Gs-dependent signals. A1R blockade by A2AR in the A1-A2AHet is not observed in the absence of A2AR activation by agonists, in the absence of the C-terminal domain of A2AR, or in the presence of synthetic peptides that disrupt the heteromer interface of A1-A2AHet, indicating that signaling mediated by A1R and A2AR is controlled by both Gi and Gs proteins.CONCLUSIONS:
We identified a new mechanism of signal transduction that implies a cross-communication between Gi and Gs proteins guided by the C-terminal tail of the A2AR. This mechanism provides the molecular basis for the operation of the A1-A2AHet as an adenosine concentration-sensing device that modulates the signals originating at both A1R and A2AR.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Receptores Purinérgicos P1
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Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP
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Subunidades alfa Gs de Proteínas de Ligação ao GTP
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Receptores Acoplados a Proteínas G
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article