GPCR heterodimers: asymmetries in ligand binding and signalling output offer new targets for drug discovery

Abstract

Dimers of GPCRs have held the imagination of researchers for almost 20 years. However, only recently has their value as potentially novel drug targets been increased significantly, and primarily, in the context of GPCR heterodimers. The view of receptor heterodimers as allosteric machines has transformed the way we understand structural and functional asymmetries inherent in their organization. These asymmetries alter both signalling output and how they might be targeted pharmacologically. The paper in this issue of BJP by Siddiquee and colleagues () highlights our growing understanding of such asymmetries and their implications. They show that heterodimers of the angiotensin II AT1 receptor and the apelin receptor recognize and respond to their respective ligands in distinct ways from the parent receptors expressed alone. Further, they demonstrate asymmetric allosteric effects in the context of the heterodimer that may have significant implications for our understanding of such receptor complexes.

Linked article: This article is a commentary on the research paper by Siddiquee et al., pp. 1104-1117 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2012.02192.x.

Figure 1

Interactions between APJ and AT1R, as described by Siddequee et al. shows how dimerization of AT1R and APJ protomers can lead to biased signalling responses downstream, via molecular cross-talk. In their model, Ap13 binding increases the affinity of each receptor for each other. The APJ protomer then inhibits, probably through conformational change, the AT1R protomer – resulting in attenuated Ang II-mediated responses – via allosteric modulation. The consequences of Ap, or concomitant Ang II/Ap binding to the dimer on downstream signalling remains to be determined. Moreover, the consequences of such allosterically biased signals on more complex phenotypic responses (hypertension, cardiac fibrosis, RAAS function, etc.), remain unknown.