Cross-conformational switching between GPCR heteromers modulate ligand efficacy. (a, b) Left panels illustrate the design of FRET sensors (filled circles CFP, open circles YFP/FlAsH) for receptor activation (a) and G protein activation (b), which are monitored by recording changes in FRET between CFP and FlAsH (or YFP); center panels show examples of activation of the α2A-AR, and the inhibitory G protein, Gi, which were monitored in a single HEK-293 cell expressing α2A-AR FlAsH/CFP (a) or the wild-type α2A-AR and GαiYFPβ1γ2CFP (b); right panels show similar experiments in cell coexpressing the μ-opioid receptor MOR. Horizontal bars indicate the application of NE or morphine to the cell. (c) Maximal NE effect on phosphorylation of ERK1/2 in cells coexpressing α2A-AR FlAsH/CFP and MOR. Note that NE acts as a partial agonist when the MOR is activated by morphine. Adapted from (13).