Basic Pharmacological and Structural Evidence for Class A G-Protein-Coupled Receptor Heteromerization

Abstract

Cell membrane receptors rarely work on isolation, often they form oligomeric complexes with other receptor molecules and they may directly interact with different proteins of the signal transduction machinery. For a variety of reasons, rhodopsin-like class A G-protein-coupled receptors (GPCRs) seem an exception to the general rule of receptor-receptor direct interaction. In fact, controversy surrounds their potential to form homo- hetero-dimers/oligomers with other class A GPCRs; in a sense, the field is going backward instead of forward. This review focuses on the convergent, complementary and telling evidence showing that homo- and heteromers of class A GPCRs exist in transfected cells and, more importantly, in natural sources. It is time to decide between questioning the occurrence of heteromers or, alternatively, facing the vast scientific and technical challenges that class A receptor-dimer/oligomer existence pose to Pharmacology and to Drug Discovery.

Keywords: GPCR; dimerization; dopamine receptor; heteromer; homodimer; ligands; mammalian receptor; signal transduction taste receptor.

FIGURE 1

Schematic representation of the T-cell receptor-CD3 complex. The heterocomplex is formed by variable TCR-α and TCR-β chains coupled to three dimeric signaling transduction modules CD3δ/ε, CD3γ/ε and CD3ζ/ζ or CD247. CD3, Cluster of differentiation 3; CD247, cluster of differentiation 247 or CD3ζ/ζ; ITAM, immunoreceptor tyrosine-based activation motif; TCR, T-cell receptor.

FIGURE 2

Scheme of the simultaneous binding of bivalent ligands with linkers of appropriate length to two receptors in a GPCR dimer. The agonist/antagonist moieties of the bivalent ligand are selective for their respective receptors (orange for GPCR-I, green for GPCR-II) and are linked by an spacer. (A) Binding to two equal GPCRs forming an homodimer. (B) Binding to two different GPCRs forming an heterodimer. A full account of the possibilities of binding of bivalent ligands to GPCRs is provided by Brogi et al. (2014).