Journal
FEBS LETTERS
Volume 595, Issue 14, Pages 1863-1875Publisher
WILEY
DOI: 10.1002/1873-3468.14135
Keywords
alpha1-adrenergic receptor; ACKR3; AVPR1A; CXCR4; receptor dimer; receptor hetero-oligomerization
Funding
- National Institutes of Health [R01GM139811, R21AA025750, R21AI139827]
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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.
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.
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