Elsevier

Pharmacology & Therapeutics

Volume 103, Issue 3, September 2004, Pages 203-221
Pharmacology & Therapeutics

Associate editor: J. Wess
GPCR interacting proteins (GIP)

https://doi.org/10.1016/j.pharmthera.2004.06.004Get rights and content

Abstract

G protein-coupled receptors (GPCR) interact not only with heterotrimeric G proteins but also with accessory proteins called GPCR interacting proteins (GIP). These proteins have important functions. They are implicated in GPCR targeting to specific cellular compartments, in their assembling into large functional complexes called “receptosomes,” in their trafficking to and from the plasma membrane, and in the fine-tuning of their signaling properties. There are several types of GIPs. Some are transmembrane proteins such as another GPCR (homodimerization and heterodimerization), ionic channels, ionotropic receptors, and single transmembrane proteins. The latter is implicated in the fine-tuning of receptor pharmacology or signaling. Other GIPs are soluble proteins interacting mainly with the “magic” C-terminal tail. Among them, PDZ domain-containing proteins are the most abundant. They generally, but not always, interact with the extreme C-terminal domain of GPCRs. Some GIPs interact with specific sequences of the C-terminal such as the Homer binding sequence (-PPxxFR-), the dopamine receptor interacting protein (DRIP) binding sequence (-FxxxFxxxF-), etc. Finally, only few GIPs have been found thus far to interact with the third intracellular loop of GPCRs. The future will tell us if this situation is only due to technical reasons.

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.

References (151)

  • H. Boudin et al.

    Molecular determinants for PICK1 synaptic aggregation and mGluR7a receptor coclustering: role of the PDZ, coiled-coil, and acidic domains

    J Biol Chem

    (2001)
  • H. Boudin et al.

    Presynaptic clustering of mGluR7a requires the PICK1 PDZ domain binding site

    Neuron

    (2000)
  • A.E. Brady et al.

    G protein-coupled receptor interacting proteins: emerging roles in localization and signal transduction

    Cell Signal

    (2002)
  • W. Cao et al.

    Direct binding of activated c-Src to the beta 3-adrenergic receptor is required for MAP kinase activation

    J Biol Chem

    (2000)
  • M. Cong et al.

    Regulation of membrane targeting of the G protein-coupled receptor kinase 2 by protein kinase A and its anchoring protein AKAP79

    J Biol Chem

    (2001)
  • L.A. Devi

    Heterodimerization of G-protein-coupled receptors: pharmacology, signaling and trafficking

    Trends Pharmacol Sci

    (2001)
  • N. Dwyer et al.

    Odorant receptor localization to olfactory cilia is mediated by ODR-4, a novel membrane-associated protein

    Cell

    (1998)
  • R. Enz

    The actin-binding protein Filamin-A interacts with the metabotropic glutamate receptor type 7

    FEBS Lett

    (2002)
  • L. Fagni et al.

    Complex interactions between mGluRs, intracellular Ca2+ stores and ion channels in neurons

    Trends Neurosci

    (2000)
  • L. Fagni et al.

    Identification and functional roles of metabotropic glutamate receptor-interacting proteins

    Cell Dev Biol

    (2004)
  • G. Fan et al.

    The scaffold protein gravin (cAMP-dependent protein kinase-anchoring protein 250) binds the beta 2-adrenergic receptor via the receptor cytoplasmic Arg-329 to Leu-413 domain and provides a mobile scaffold during desensitization

    J Biol Chem

    (2001)
  • G.J. Feng et al.

    Selective interactions between helix VIII of the human mu-opioid receptors and the C terminus of periplakin disrupt G protein activation

    J Biol Chem

    (2003)
  • I.D. Fraser et al.

    Assembly of an A kinase-anchoring protein-beta(2)-adrenergic receptor complex facilitates receptor phosphorylation and signaling

    Curr Biol

    (2000)
  • T. Galvez et al.

    Mapping the agonist-binding site of GABAB type 1 subunit sheds light on the activation process of GABAB receptors

    J Biol Chem

    (2000)
  • R. Golser et al.

    Interaction of endothelial and neuronal nitric-oxide synthases with the bradykinin B2 receptor. Binding of an inhibitory peptide to the oxygenase domain blocks uncoupled NADPH oxidation

    J Biol Chem

    (2000)
  • I. Guillet-Deniau et al.

    Identification and localization of a skeletal muscle serotonin 5-HT2A receptor coupled to the Jak/STAT pathway

    J Biol Chem

    (1997)
  • H. Hamm

    The many faces of G protein signaling

    J Biol Chem

    (1998)
  • L. Hicke et al.

    Ubiquitination of a yeast plasma membrane receptor signals its ligand-stimulated endocytosis

    Cell

    (1996)
  • T. Hirakawa et al.

    GIPC binds to the human lutropin receptor (hLHR) through an unusual PDZ domain binding motif, and it regulates the sorting of the internalized human choriogonadotropin and the density of cell surface hLHR

    J Biol Chem

    (2003)
  • H. Hirbec et al.

    The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs

    J Biol Chem

    (2002)
  • G. Hjalm et al.

    Filamin-A binds to the carboxyl-terminal tail of the calcium-sensing receptor, an interaction that participates in CaR-mediated activation of mitogen-activated protein kinase

    J Biol Chem

    (2001)
  • L.A. Hu et al.

    beta 1-adrenergic receptor association with PSD-95. Inhibition of receptor internalization and facilitation of beta 1-adrenergic receptor interaction with N-methyl-d-aspartate receptors

    J Biol Chem

    (2000)
  • L.A. Hu et al.

    GIPC interacts with the beta1-adrenergic receptor and regulates beta1-adrenergic receptor-mediated ERK activation

    J Biol Chem

    (2003)
  • H. Ju et al.

    Inhibitory interactions of the bradykinin B2 receptor with endothelial nitric-oxide synthase

    J Biol Chem

    (1998)
  • A. Kato et al.

    vesl, a gene encoding VASP/Ena family related protein is upregulated during seizure, long-term potentiation and synaptogenesis

    FEBS Lett

    (1997)
  • J. Kitano et al.

    Direct interaction and functional coupling between metabotropic glutamate receptor subtype 1 and voltage-sensitive Cav2.1 Ca2+ channel

    J Biol Chem

    (2003)
  • H.J. Kreienkamp

    Organisation of G-protein-coupled receptor signalling complexes by scaffolding proteins

    Curr Opin Pharmacol

    (2002)
  • F.J. Lee et al.

    Dual regulation of NMDA receptor functions by direct protein-protein interactions with the dopamine D1 receptor

    Cell

    (2002)
  • J.G. Li et al.

    Ezrin-radixin-moesin-binding phosphoprotein-50/Na+/H+ exchanger regulatory factor (EBP50/NHERF) blocks U50,488H-induced down-regulation of the human kappa opioid receptor by enhancing its recycling rate

    J Biol Chem

    (2002)
  • Y. Liang et al.

    Organization of the G protein-coupled receptors rhodopsin and opsin in native membranes

    J Biol Chem

    (2003)
  • F. Lin et al.

    Gravin-mediated formation of signaling complexes in beta 2-adrenergic receptor desensitization and resensitization

    J Biol Chem

    (2000)
  • J. Loconto et al.

    Functional expression of murine V2R pheromone receptors involves selective association with the M10 and M1 families of MHC class Ib molecules

    Cell

    (2003)
  • N.P. Martin et al.

    Regulation of V2 vasopressin receptor degradation by agonist-promoted ubiquitination

    J Biol Chem

    (2003)
  • P.H. McDonald et al.

    Beta-Arrestins: new roles in regulating heptahelical receptors' functions

    Cell Signal

    (2001)
  • G. Milligan et al.

    Protein-protein interactions at G-protein-coupled receptors

    Trends Pharmacol Sci

    (2001)
  • M. Morfis et al.

    RAMPs: 5 years on, where to now?

    Trends Pharmacol Sci

    (2003)
  • R.B. Nehring et al.

    The metabotropic GABAB receptor directly interacts with the activating transcription factor 4 (ATF-4)

    J Biol Chem

    (2000)
  • G. Nelson et al.

    Mammalian sweet taste receptors

    Cell

    (2001)
  • S. Angers et al.

    Dimerization: an emerging concept for G protein-coupled receptor ontogeny and function

    Annu Rev Pharmacol Toxicol

    (2002)
  • F. Ango et al.

    Dendritic and axonal targeting of type 5 metabotropic glutamate receptor is regulated by Homer1 proteins and neuronal excitation

    J Neurosci

    (2000)
  • Cited by (0)

    View full text