Associate editor: J. WessGPCR interacting proteins (GIP)
Introduction
During evolution, “molecular tinkering” of G protein-coupled receptors (GPCR) has proven to be greatly successful (Bockaert & Pin, 1999, Bockaert et al., 2002, Fredriksson et al., 2003). This “tinkering” has provided more than 1000 GPCRs dedicated not only to cell-cell communication but also to the recognition of environmental signals such as light, smell, and tastes from a single gene or a limited number of genes. GPCR signal transduction implicates a limited number of heterotrimeric G proteins that regulate second messenger production and channel ionic activity. However, the evolution process did not stop there. Producing new molecules or “modifying” already available ones has been necessary to ensure other important GPCR functions such as (1) GPCR targeting to the right subcellular compartment; (2) association of GPCRs with other cellular molecules, named scaffolding molecules, which allow functional signaling machinery to be assembled; (3) regulation of GPCR trafficking to and from the plasma membrane; and (4) fine-tuning of GPCR signaling.
A few years ago, the life of the GPCRs' groupies was very simple. The scenario of GPCR action was the following. GPCRs are activated by their specific ligands, leading to conformational changes within the transmembrane and intracellular domains. This process provides a way for the receptor to interact with one or several heterotrimeric G proteins. A GDP to GTP exchange takes place within the G proteins, leading to a dissociation between Gα-GTP and Gβγ subunits (Hamm, 1998). Both subunits were able to bind and regulate various intracellular effectors. However, GPCRs are now recognized to interact with many other proteins (GPCR interacting proteins [GIP]). Indeed, since the discovery of inactivation-no-afterpotential D (INAD; Montell, 1997, Huber, 2001), Ste5 (Ptashne & Gann, 1998, Park et al., 2003), and arrestins “receptosomes” (McDonald & Lefkowitz, 2001, Pierce et al., 2002), a considerable number of GIPs have been described (Hall et al., 1999, Milligan & White, 2001, Brady & Limbird, 2002, El Far & Betz, 2002, Kreienkamp, 2002, Bockaert et al., 2003, Fagni et al., 2004). As we will review here, these GIPs are implicated in most of the aforementioned GPCR cellular functions (Table 1).
Section snippets
The birth of the ≪receptosome≫ concept
In this first chapter, we will describe several examples of multiprotein complexes implicated in GPCR signaling whose functions are particularly well characterized.
Transmembrane G protein-coupled receptor interacting proteins
In this section and those that follow, we will describe direct interactions between GPCRs and individual GIPs and, when possible, the functions of these interactions. However, as opposed to the previous examples, less effort will be made to integrate these interactions within important signaling networks. In the future, this should be done using specific and global bioinformatic tools.
Soluble G protein-coupled receptor interacting proteins interacting with G protein-coupled receptor C-termini
There is increasing evidence that the “magic tail” of GPCRs constitutes the main anchoring domain for soluble GIPs (more than 50 GIPs interacting with GPCR C-termini have been identified; Bockaert et al., 2003). Here, we will distinguish between proteins that interact with the PDZ ligand located at the extreme C-terminus and those that recognize motifs upstream of the PDZ ligand.
G protein-coupled receptor interacting proteins that interact with the i3 loop of G protein-coupled receptors
Although the i3 loop is one of the most important domains of GPCRs for their interaction with G proteins, relatively few GIPs have been shown to interact thus far at this level. One reason for this is that the yeast 2-hybrid approaches that have been used in many studies work better with the “magic tails.” The i3 loops, in contrast to the C-tails, are unlikely to adopt native conformations when isolated from the rest of the receptor.
Several cytoskeletal-associated proteins interact with the i3
Conclusion
It is now evident that signaling specificity of a GPCR is dependent not only on the nature of the heterotrimeric G proteins to which it is coupled but also on the nature of the GIPs to which it binds. The nature of these GIPs will determine its targeting to a specific cellular compartment, its association with other signaling or structural proteins, and the fine-tuning of its signal transduction including desensitization and resensitization. The natures of these GIPs are evidently different,
Acknowledgment
We would like to thank the European Union EC STREP for the grant no. 503 337 “Functional Pharmacogenomics of GPCRs.” Supported by Centre National de la Recherche Scientifique (CNRS) and Génopole Montpellier-languedoc Roussillon.
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