Associate editor: Ulrik GetherDimers and beyond: The functional puzzles of class C GPCRs
Introduction
GPCRs are key cell-surface receptors for cellular adaptation to their environment and are sensitive to a large array of stimuli including light (photons), amino acids and large proteins. Approximately 800 genes (more than 3% of the human genome) encode for such receptors and they represent an important market for pharmaceutical companies. A common feature for these receptors is a large transmembrane core composed of seven helices with an extracellular N-terminus and an intracellular C-terminal tail. Based on the phylogeny of the transmembrane core (7TM), GPCRs have been classified in 3 main families: classes A, B and C. Despite a similar role (converting an extracellular stimulus into a cellular response via activation of G protein or other signaling cascades), the precise activation mechanisms differ from class to class, mainly due to structural differences. The present review will only focus on class C GPCRs.
Class C consists of the receptors for glutamate (mGlu receptors), GABA (GABAB receptors), Ca2+ ions (CaS receptor), sweet and umami tastes (T1Rs), basic amino acids (GPRC6a) and some orphan receptors (GPR156, GPR158, GPR179 and RAIG) (Fig. 1). A structural feature shared by most of these receptors, is a large, structurally-defined extracellular domain called the Venus flytrap (VFT). This domain is constituted of two opposing lobes, separated by a cleft where the endogenous ligands bind. Such particular protein folding is shared with periplasmic binding proteins and is also found in other cell surface receptors such as ligand-gated ion channels, tyrosine kinase or guanylate cyclase receptors. A second characteristic of class C GPCRs is their constitutive dimerization at the cell-surface as either homodimers (mGlu and CaS) or heterodimers (GABAB and T1Rs) by association between two identical or non-identical proteins, respectively. The homodimeric receptors were shown to be covalently linked by a disulphide bridge in the region of their VFT (Romano et al., 1996, Bai et al., 1998). Heterodimeric receptors are not covalently linked, but their heterodimerization is required to obtain a functional dimer as one of the subunits contains the endogenous ligand binding site, whilst the other mediates signal transduction (Galvez et al., 2001, Margeta-Mitrovic et al., 2001, Nelson et al., 2001, Nelson et al., 2002). The significance of dimerization of class C GPCRs on the activation mechanisms has been studied over the last years.
Like many other GPCRs, class C receptors have been described to be part of larger oligomeric complexes, either with themselves, with other GPCRs or with unrelated cell-surface receptors. This can involve direct interaction or participation in complexes with multiple different proteins, either scaffolding or signaling proteins, resulting in cross-talk of signaling pathways. The characterization of these complexes has yet to be fully defined with regard to understanding their function in their native environment. Elucidation of such information would be of critical importance for therapeutic purposes. Indeed, while class C GPCRs are implicated in many physiological functions and pathological disorders, only a few therapeutic compounds target these receptors, mainly due to a lack of knowledge of the precise function.
In this review, we will present the molecular mechanisms of class C GPCRs activation and of their modulation, the functional significance of receptor association in larger complexes, in addition to reporting on the clinical studies conducted on these receptors, in order to illustrate their therapeutic interest.
Section snippets
Class C GPCRs: family members
The first members of the family to be cloned were the metabotropic glutamate receptors (Houamed et al., 1991, Masu et al., 1991). These receptors are activated by glutamate, the major excitatory neurotransmitter of the central nervous system (CNS), and thus participate in regulating the cell excitability and synaptic transmission. Eight subtypes of receptors have been identified so far and are classified in three groups based on their sequence, localization and signaling pathways. Group-I (mGlu1
Class C GPCRs mechanisms of action
As previously mentioned, class C GPCRs form constitutive dimers. It is becoming more apparent that dimer formation is mandatory for the function of these receptors, making them complex allosteric proteins where each domain influences the neighboring ones, such that a conformational change in one domain will facilitate changes in others. As abovementioned, in addition to the common 7TM most class C GPCRs are characterized by the presence of a large VFT extracellular domain (Fig. 1A). This domain
Class C GPCR complexes
Oligomerization of GPCRs has been described for about 20 years now, but the functional impact of that phenomenon have been the subject of intense debate (for review see (Chabre et al., 2009, Gurevich and Gurevich, 2008a, Gurevich and Gurevich, 2008b). Despite that in a purified lipid environment all studied receptors could activate G proteins as a monomer, transcomplementation experiments performed in cells support that dimers are indeed the signaling entities. Regarding class C GPCRs, their
Therapeutic potential of class C GPCRs
These past few years many reviews have been written about the implication in physiopathology of receptors belonging to class C, especially mGlu, GABAB and CaS receptors. In the present chapter, the therapeutic interest of these receptors will be illustrated through examples of clinical studies targeting class C GPCRs. For more details on preclinical studies involving these receptors, we invite the reader to refer to the review articles cited below.
Concluding remarks
As described here, the unique structural features of class C GPCRs are reflected in their particular molecular mechanisms of action. In a simplistic view, these receptors are dimeric with each protomer composed of two or three well separate domains, but all communicate as an ensemble to activate or inhibit their cognate signaling molecules. Class C GPCRs signaling can also be modulated by the presence of other receptors in the local environment. Whilst there remains much to do in order to
Acknowledgments
We would like to thank Dr. Gregory D. Stewart for critical reading of the manuscript and English editing. This work was supported by CNRS, INSERM, Cisbio and by grants from the French Ministry of Research, Action Concertée Incitative “Biologie Cellulaire Moléculaire et Structurale” (ACI-BCMS 328), the Agence Nationale de la Recherche (ANR-05-PRIB-02502, ANR-BLAN06-3_135092, ANR-05-NEUR-035 and ANR-NT09-481664), and by an unrestricted grant from Senomyx (La Jolla, CA, USA).
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