Dimerization: An Emerging Concept for G Protein–Coupled Receptor Ontogeny and Function

Abstract

In the last four to five years, the view that G protein-coupled receptors (GPCRs) function as monomeric proteins has been challenged by numerous studies, which suggests that GPCRs exist as dimers or even higher-structure oligomers. Recently, biophysical methods based on luminescence and fluorescence energy transfer have confirmed the existence of such oligomeric complexes in living cells. Although no consensus exists on the role of receptor dimerization, converging evidence suggests potential roles in various aspects of receptor biogenesis and function. In several cases, receptors appear to fold as constitutive dimers early after biosynthesis, whereas ligand-promoted dimerization at the cell surface has been proposed for others. The reports of heterodimerization between receptor subtypes suggest a potential level of receptor complexity that could account for previously unexpected pharmacological diversities. In addition to fundamentally changing our views on the structure and activation processes of GPCRs, the concept of homo- and heterodimerization could have dramatic impacts on drug development and screening.

Cell-surface targeting of α2-adrenergic receptors — Inhibition by a transport deficient mutant through dimerization

“…Furthermore, α 2A -AR and α 2C -AR indeed form heterodimers with β 1 -AR and M 3 -muscarinc receptor, respectively [40,41]. As homo-and hetero-dimerization may play a crucial role in the regulation of cell-surface targeting, signaling specificity/efficiency and ligand binding selectivity of individual receptors [34], the finding that α 2B -AR exists in dimeric forms and possible heterodimerization between different α 2 -AR subtypes hints at the complexity of α 2 -AR and may open additional ways of understanding the function of this subfamily of G protein-coupled receptors.…”

“…Therefore, dimers are unable to export from the ER. Dimerization has been well described for a variety of G protein-coupled receptors [9][10][11][12][13][14][15][34][35][36][37][38][39][40][41]. However, whether α 2B -AR is capable of forming homodimers has not been reported.…”

Kinin B1 receptor homo-oligomerization is required for receptor trafficking to the cell surface

“…Considerable evidence now exist that G protein-coupled receptor (GPCR) homooligomerization is required for receptors to exit the ER and traffick to the plasma membrane [15,16]. Indeed, GPCR oligomerization is emerging as a novel therapeutic target [17,18].…”

Métaphores, nomenclature et nouveaux paradigmes de signalisation par les récepteurs couplés aux protéines G

“…Cette dimension plurielle de l'efficacité de signalisation des RCPG offre toutefois de nouvelles opportunités pour le développement de médi-caments plus efficaces et ayant moins d'effets indésirables, en ciblant sélectivement les voies de signalisations importantes pour leur action thérapeutique. La constatation que, contrairement à ce qui était générale-ment admis, les RCPG ne sont pas que des protéines monomé-riques, mais peuvent former des dimères, voire des oligomères de plus grande taille, offre aussi de nouvelles perspectives pour le développement de thérapies innovantes [9,10]. En particulier, l'existence d'hétérodimères formés de sous-types de récepteurs distincts, qui acquièrent des propriétés pharmacologiques et de signalisation différentes de celles de chacun des protomères, ouvre la porte au développement de composés qui ciblent sélectivement certains hétérodimères pour des indications cliniques précises.…”