G-protein-coupled receptor heterodimerization modulates receptor function

The opioid system modulates several physiological processes, including analgesia, the stress response, the immune response and neuroendocrine function 1 . Pharmacological and molecular cloning studies have identified three opioid-receptor types, δ, κ and µ, that mediate these diverse effects 2 , 3 . Little is known about the ability of the receptors to interact to form new functional structures, the simplest of which would be a dimer. Structural and biochemical studies show that other G-protein-coupled receptors (GPCRs) interact to form homodimers 4 , 5 . Moreover, two non-functional receptors heterodimerize to form a functional receptor, suggesting that dimerization is crucial for receptor function 6 , 7 , 8 , 9 , 10 , 11 . However, heterodimerization between two fully functional receptors has not been documented. Here we provide biochemical and pharmacological evidence for the heterodimerization of two fully functional opioid receptors, κ and δ. This results in a new receptor that exhibits ligand binding and functional properties that are distinct from those of either receptor. Furthermore, the κ–δ heterodimer synergistically binds highly selective agonists and potentiates signal transduction. Thus, heterodimerization of these GPCRs represents a novel mechanism that modulates their function.