G protein-coupled receptor hetero-dimerization: contribution to pharmacology and function

Abstract

The concept that G protein-coupled receptors (GPCRs) can form hetero-dimers or hetero-oligomers continues to gain experimental support. However, with the exception of the GABA(B) receptor and the sweet and umami taste receptors few reported examples meet all of the criteria suggested in a recent International Union of Basic and Clinical Pharmacology sponsored review (Pin et al., 2007) that should be required to define distinct and physiologically relevant receptor species. Despite this, there are many examples in which pairs of co-expressed GPCRs reciprocally modulate their function, trafficking and/or ligand pharmacology. Such data are at least consistent with physical interactions between the receptor pairs. In recent times, it has been suggested that specific GPCR hetero-dimer or hetero-oligomer pairs may represent key molecular targets of certain clinically effective, small molecule drugs and there is growing interest in efforts to identify ligands that may modulate hetero-dimer function selectively. The current review summarizes key recent developments in these topics.

Figure 1

The α_1B-adrenoceptor traffics to the cell surface as a dimer/oligomer. A form of the α_1B-adrenoceptor containing mutations in transmembrane domains (TM) I and IV (α_1BTMITMIV, blue) (Lopez-Gimenez et al., 2007) is retained in the endoplasmic reticulum (ER) when expressed in HEK293 (human embryonic kidney) cells and study employing bimolecular fluorescence complementation indicate that it exists as a dimer/oligomer (Lopez-Gimenez et al., 2007). Sustained treatment of such cells with the α₁-adrenoceptor antagonist prazosin results in maturation of the receptor and its movement to the plasma membrane (PM). A form of the α_1B-adrenoceptor that is wild-type except that it contains an Asp¹²⁵Ala mutation that eliminates its ability to bind prazosin (α_1BD¹²⁵A, yellow) is delivered successfully to the PM when expressed. When α_1BD¹²⁵A is co-expressed with α_1BTMITMIV, α_1BD¹²⁵A becomes ER-retained because α_1BTMITMIV interacts with α_1BD¹²⁵A and functions as a ‘dominant negative’. Treatment of these cells with prazosin results in movement of both α_1BTMITMIV and α_1BD¹²⁵A to the cell surface. As α_1BD¹²⁵A cannot bind prazosin, these observations indicate that the two forms of the α_1B-adrenoceptor move to the PM as a dimer/oligomer (see Canals et al., 2009 for further details).