The pivotal position of G-protein-coupled receptors (GPCRs) in cell-signalling pathways means they are attractive drug targets; indeed, over 50% of current drugs directly affect GPCRs. As early as the mid-1970s, it was proposed that GPCRs might form dimers or oligomers, but it is only recently that the idea has become more generally accepted. Nevertheless, much remains to be elucidated about the functional significance of dimerization; for example, whether it is necessary for receptor activation and how widespread it is among different GPCR families. By analysing the wealth of GPCR and G-protein sequences in combination with structural data, Christopher Reynolds and co-workers have provided evidence that several key GPCR families contain functional interfaces consistent with dimerization, and that a putative receptor-binding site on G proteins is consistent with binding to a GPCR dimer.

Members of the GPCR superfamily all share the same basic architecture — seven transmembrane a-helices, an extracellular amino-terminal segment and an intracellular carboxy-terminal tail. Reynolds and colleagues used the evolutionary trace (ET) method to infer the location of functional sites within different GPCR families. Essentially, this data-mining method identifies amino-acid residues with high levels of conservation. These family-specific 'trace' residues are then mapped on to a representative superfamily structure. Clustering of trace residues indicates sites that are likely to impart functional specificity to family members.

The seven families studied include many important drug targets, such as β-adrenergic receptors, histamine receptors, opioid receptors and dopamine receptors. ET analysis of the ∼700 GPCR sequences available predicted functionally important clusters on the external faces of helices 5 and 6 for each family. Much other evidence has indicated the presence of a dimerization interface between helices 5 and 6 — these ET results both add support to this idea and further suggest that all the GPCRs studied could dimerize by a common mechanism. Moreover, ET analysis of ∼100 G proteins suggested that the potential GPCR-binding site has the appropriate size and electrostatic properties for binding to a dimer. Finally, the ET analysis of the GPCRs indicated further functional clusters on the external faces of helices 2 and 3, which the authors suggest could allow GPCRs to form higher-order oligomers or could be involved in interactions with other proteins, such as ion channels.

The possibilities raised by GPCR homo- and heterodimerization vastly increase the potential pharmacological diversity of this family, and have important implications for the discovery of new drugs that target these receptors; for example, assays that test potential GPCR modulators could involve multiple receptors. Exploitation of these phenomena could be a very promising route to more selective and efficacious drugs in this key class.