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 mu opioid receptor (mu OR), is of great clinical relevance. Here we show that heterodimerization of mu OR with delta opioid receptors (delta OR) leads to a constitutive recruitment of beta-arrestin2 to the receptor complex resulting in changes in the spatiotemporal regulation of ERK1/2 signaling. The involvement of beta-arrestin2 is further supported by studies using beta-arrestin2 siRNA in cells endogenously expressing the heterodimers. The association of beta-rrestin2 with the heterodimer can be altered by treatment with a combination of mu OR agonist (DAMGO) and delta OR antagonist (Tipp psi), and this leads to a shift in the pattern of ERK1/2 phosphorylation to the pattern observed with mu OR alone. These data indicate that, in the naive state, mu OR- delta OR heterodimers are in a conformation conducive to beta-arrestin-mediated signaling. Destabilization of this conformation by cotreatment with mu OR and delta OR ligands leads to a switch to a non-beta-arrestin- mediated signaling. Taken together, these results show for the first time that mu OR- delta OR heterodimers, by differentially recruiting beta-arrestin, modulate the spatio-temporal dynamics of opioid receptor signaling.