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Cross-communication between G i and G s in a G-protein-coupled receptor heterotetramer guided by a receptor C-terminal domain.

Authors :
Navarro G
Cordomí A
Brugarolas M
Moreno E
Aguinaga D
Pérez-Benito L
Ferre S
Cortés A
Casadó V
Mallol J
Canela EI
Lluís C
Pardo L
McCormick PJ
Franco R
Source :
BMC biology [BMC Biol] 2018 Feb 28; Vol. 16 (1), pp. 24. Date of Electronic Publication: 2018 Feb 28.
Publication Year :
2018

Abstract

Background: G-protein-coupled receptor (GPCR) heteromeric complexes have distinct properties from homomeric GPCRs, giving rise to new receptor functionalities. Adenosine receptors (A <subscript>1</subscript> R or A <subscript>2A</subscript> R) can form A <subscript>1</subscript> R-A <subscript>2A</subscript> R heteromers (A <subscript>1</subscript> -A <subscript>2A</subscript> Het), and their activation leads to canonical G-protein-dependent (adenylate cyclase mediated) and -independent (β-arrestin mediated) signaling. Adenosine has different affinities for A <subscript>1</subscript> R and A <subscript>2A</subscript> R, allowing the heteromeric receptor to detect its concentration by integrating the downstream G <subscript>i</subscript> - and G <subscript>s</subscript> -dependent signals. cAMP accumulation and β-arrestin recruitment assays have shown that, within the complex, activation of A <subscript>2A</subscript> R impedes signaling via A <subscript>1</subscript> R.<br />Results: We examined the mechanism by which A <subscript>1</subscript> -A <subscript>2A</subscript> Het integrates G <subscript>i</subscript> - and G <subscript>s</subscript> -dependent signals. A <subscript>1</subscript> R blockade by A <subscript>2A</subscript> R in the A <subscript>1</subscript> -A <subscript>2A</subscript> Het is not observed in the absence of A <subscript>2A</subscript> R activation by agonists, in the absence of the C-terminal domain of A <subscript>2A</subscript> R, or in the presence of synthetic peptides that disrupt the heteromer interface of A <subscript>1</subscript> -A <subscript>2A</subscript> Het, indicating that signaling mediated by A <subscript>1</subscript> R and A <subscript>2A</subscript> R is controlled by both G <subscript>i</subscript> and G <subscript>s</subscript> proteins.<br />Conclusions: We identified a new mechanism of signal transduction that implies a cross-communication between G <subscript>i</subscript> and G <subscript>s</subscript> proteins guided by the C-terminal tail of the A <subscript>2A</subscript> R. This mechanism provides the molecular basis for the operation of the A <subscript>1</subscript> -A <subscript>2A</subscript> Het as an adenosine concentration-sensing device that modulates the signals originating at both A <subscript>1</subscript> R and A <subscript>2A</subscript> R.

Details

Language :
English
ISSN :
1741-7007
Volume :
16
Issue :
1
Database :
MEDLINE
Journal :
BMC biology
Publication Type :
Academic Journal
Accession number :
29486745
Full Text :
https://doi.org/10.1186/s12915-018-0491-x