Do orphan G-protein-coupled receptors have ligand-independent functions? New insights from receptor heterodimers

Abstract

G-protein-coupled receptors (GPCRs) are important drug targets and are involved in virtually every biological process. However, there are still more than 140 orphan GPCRs, and deciphering their function remains a priority for fundamental and clinical research. Research on orphan GPCRs has concentrated mainly on the identification of their natural ligands, whereas recent data suggest additional ligand-independent functions for these receptors. This emerging concept is connected with the observation that orphan GPCRs can heterodimerize with GPCRs that have identified ligands, and by so doing regulate the function of the latter. Pairing orphan GPCRs with their potential heterodimerization partners will have a major impact on our understanding of the extraordinary diversity offered by GPCR heterodimerization and, in addition, will constitute a novel strategy to elucidate the function of orphan receptors that needs to be added to the repertoire of 'deorphanization' strategies.

Figure 1

Possible ligand-independent functions of orphan seven-transmembrane proteins in heterodimers. (A) Signalling and internalization of G-protein-coupled receptor (GPCR) dimers with known ligands controlled by regulating molecules (including G proteins, β-arrestins, regulators of G-protein signalling, Homer family proteins and PDZ-domain-containing proteins). (B) Regulation of the export of GPCRs with known ligands to the cell surface by orphan seven-transmembrane (7TM) proteins. Heterodimerization might promote surface expression of the functional heterodimer or retain the heterodimer in intracellular compartments. (C) Increase or induction of the interaction of non-orphan GPCRs with intracellular regulators in the same or different signalling pathways (compared with the non-orphan GPCR homodimer) by orphan 7TM proteins. (D) Inhibition of receptor internalization or the interaction of non-orphan GPCRs with intracellular regulators by orphan 7TM proteins. (E) Modulation of the ligand-binding properties of the non-orphan protomer compared with the corresponding homodimer by orphan 7TM proteins. (F) Orphan GPCRs could have constitutive activity and thus ligand-independent functions. GPCRs with known ligand (pale pink); orphan GPCR (dark blue); intracellular regulators (turquoise); ligands (orange). ER, endoplamic reticulum.

Figure 2

Signalling properties of orphan/non-orphan heterodimers versus non-orphan homodimers. (A) Stimulation of MrgD homodimers with β-alanine promotes MrgD internalization, ERK activation and the transient elevation of intracellular calcium concentration. Expression with the orphan MrgE potentiates ERK activation, allows β-alanine to elicit a sustained increase in intracellular calcium levels, and inhibits MrgD internalization. (B) Stimulation of MT₁ homodimers with melatonin increases coupling to inhibitory G_i proteins and β-arrestin recruitment, and inhibits cAMP accumulation. Coexpression with the orphan GPR50 prevents β-arrestin and G_i protein interaction probably owing to steric hindrance caused by the long carboxy-terminal tail of GPR50. In the absence of functional G-protein coupling, the MT₁ protomer is devoid of high-affinity agonist binding. β-Ala, β-alanine; ERK, extracellular-signal-regulated kinase; GPCR, G-protein-coupled receptor; GPR50, G-protein-coupled receptor 50; MLT, melatonin; Mrg, Mas-related gene; MT, melatonin receptor.

Jean-Luc Guillaume, Angélique Levoye, Julie Dam, Ralf Jockers &Mohammed A. Ayoub