Abstract
Since its development, the bioluminescence resonance energy transfer (BRET) approach has been extensively applied to study G protein-coupled receptors (GPCRs) in real-time and in live cells. One of the major aspects of GPCRs investigated in considerable details is their physical coupling to the heterotrimeric G proteins. As a result, new concepts have emerged, but few questions are still a matter of debate illustrating the complexity of GPCR-G protein interactions and coupling. Here, we summarized the recent advances on our understanding of GPCR-G protein coupling based on BRET approaches and supported by other FRET-based studies. We essentially focused on our recent studies in which we addressed the concept of preassembly vs. the agonist-dependent interaction between the protease-activated receptor 1 (PAR1) and its cognate G proteins. We discussed the concept of agonist-induced conformational changes within the preassembled PAR1-G protein complexes as well as the critical question how the multiple coupling of PAR1 with two different G proteins, Gαi1 and Gα12, but also β-arrestin 1, can be regulated.
Highlights
G protein-coupled receptors (GPCRs) constitute one of the largest cell surface receptor family, and are involved in many cellular signaling and physiological responses (Bockaert, 1991; Gether, 2000)
We focus on the recent studies using the bioluminescence resonance energy transfer (BRET) approach to investigate the physical and functional interaction between GPCRs and the heterotrimeric G proteins taking lessons from our observations on the interaction of the thrombin receptor, protease-activated receptor 1 (PAR1), with Gαi1 and Gα12 as well as β-arrestin 1 (Ayoub et al, 2007, 2009, 2010)
We found that the constitutive BRET signal was completely insensitive to pertussis toxin (PTX) treatment which inhibits the Gαi1 protein activation (Ayoub et al, 2007, 2010), such that the assembly observed had nothing to do with G protein activation
Summary
G protein-coupled receptors (GPCRs) constitute one of the largest cell surface receptor family, and are involved in many cellular signaling and physiological responses (Bockaert, 1991; Gether, 2000). GPCR-G protein preassembly may allow a better control of the selectivity of the signaling cascades since one would argue that a preassembled receptor has a limited availability in space (same tissue or cell) and in time (simultaneously) to interact and couple to different G proteins as we nicely demonstrated for PAR1 and Gαi1 and Gα12 (Ayoub et al, 2010).
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