Roles of G-protein-coupled receptor dimerization

Abstract

The classical idea that G-protein-coupled receptors (GPCRs) function as monomeric entities has been unsettled by the emerging concept of GPCR dimerization. Recent findings have indicated not only that many GPCRs exist as homodimers and heterodimers, but also that their oligomeric assembly could have important functional roles. Several studies have shown that dimerization occurs early after biosynthesis, suggesting that it has a primary role in receptor maturation. G-protein coupling, downstream signalling and regulatory processes such as internalization have also been shown to be influenced by the dimeric nature of the receptors. In addition to raising fundamental questions about GPCR function, the concept of dimerization could be important in the development and screening of drugs that act through this receptor class. In particular, the changes in ligand-binding and signalling properties that accompany heterodimerization could give rise to an unexpected pharmacological diversity that would need to be considered.

Figure 1. Potential roles of G-protein-coupled receptor (GPCR) dimerization during the GPCR life cycle.

(1) In some cases, dimerization has been shown to have a primary role in receptor maturation and allows the correct transport of GPCRs from the endoplasmic reticulum (ER) to the cell surface. (2) Once at the plasma membrane, dimers might become the target for dynamic regulation by ligand binding. (3) It has been proposed that GPCR heterodimerization leads to both positive (+) and negative (−) ligand binding cooperativity, as well as (4) potentiating (+)/attenuating (−) signalling or changing G-protein selectivity. (5) Heterodimerization can promote the co-internalization of two receptors after the stimulation of only one protomer. Alternatively, the presence of a protomer that is resistant to agonist-promoted endocytosis, within a heterodimer, can inhibit the internalization of the complex. G, G protein; L, ligand.