Figure 3.

This illustration represents the hypothetical mechanism underlying domain swapping between two GPCRs. This proposed mechanism primarily pertains to receptors within the same subtypes, such as dopamine D2 and D3, as well as muscarinic M2 and M3 receptors. The process involves the exchange of transmembrane regions VI and VII between these two receptors, visually portrayed by the interchange of the cylindrical segments in the diagram. This intriguing phenomenon can result in either a modification of drug selectivity, evident through the distinct colors denoting ligands bound to the receptors, or an alteration in G protein coupling selectivity. This selectivity shift is visualized by the differing colors representing G proteins bound to the receptors, whether in their monomeric or heterodimeric forms. It is worth noting that this model, as well as class A GPCR dimerization per se, is highly controversial. In fact, all structures of the complexes of GPCRs with G proteins, arrestins, and of rhodopsin with GRK1, reveal a single GPCR bound to one molecule of a signaling protein. Class C GPCRs are true dimers, but they function without domain swapping. Nevertheless, as indicated in the text, the phenomenon of domain swapping has been leveraged in vivo to rescue the function of defective GPCRs.