Class A G protein-coupled receptors assemble into functional higher-order hetero-oligomers

Although class A seven-transmembrane helix (7TM) receptor hetero-oligomers have been proposed, information on the assembly and function of such higher-order hetero-oligomers is not available. Utilizing bioluminescence resonance energy transfer (BRET), bimolecular luminescence/fluorescence complementation (BiLC/BiFC), and BiLC/BiFC BRET in HEK293T cells, we provide evidence that chemokine (C-X-C motif) receptor 4, atypical chemokine receptor 3, alpha(1a)-adrenoceptor, and arginine vasopressin receptor 1A form hetero-oligomers composed of 2-4 different protomers. We show that hetero-oligomerization per se and ligand binding to individual protomers regulate agonist-induced coupling to the signaling transducers of interacting receptor partners. Our findings support the concept that receptor hetero-oligomers form supramolecular machineries with molecular signaling properties distinct from the individual protomers. These findings provide a mechanism for the phenomenon of context-dependent receptor function.

Automated summary

This study utilized various biotechniques to confirm that chemokine receptor 4, atypical chemokine receptor 3, alpha(1a)-adrenoceptor, and arginine vasopressin receptor 1A can form hetero-oligomers composed of 2-4 different protomers, with ligand binding and hetero-oligomerization regulating agonist-induced signaling transduction. These findings suggest that receptor hetero-oligomers have unique signaling properties different from individual protomers, providing a mechanism for context-dependent receptor function.