Receptor heterodimerization leads to a switch in signaling: β-arrestin2-mediated ERK activation by μ-δ opioid receptor heterodimers

Opiates are analgesics of choice in the treatment of chronic pain, but their long-term use leads to the development of physiological tolerance. Thus, understanding the mechanisms modulating the response of their receptor, the μ opioid receptor (μOR), is of great clinical relevance. Here we show that heterodimerization of μOR with δ opioid receptors (δOR) leads to a constitutive recruitment of β-arrestin2 to the receptor complex resulting in changes in the spatiotemporal regulation of ERK1/2 signaling. The involvement of β-arrestin2 is further supported by studies using β-arrestin2 siRNA in cells endogenously expressing the heterodimers. The association of β-arrestin2 with the heterodimer can be altered by treatment with a combination of μOR agonist (DAMGO) and δOR antagonist (TippΨ), and this leads to a shift in the pattern of ERK1/2 phosphorylation to the pattern observed with μOR alone. These data indicate that, in the naive state, μOR-δOR heterodimers are in a conformation conducive to β-arrestin-mediated signaling. Destabilization of this conformation by cotreatment with μOR and δOR ligands leads to a switch to a non-β-arrestin-mediated signaling. Taken together, these results show for the first time that μOR-δOR heterodimers, by differentially recruiting β-arrestin, modulate the spatio-temporal dynamics of opioid receptor signaling.