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opioid receptor heterodimersDepartment of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York, USA
1Correspondence: Department of Pharmacology and Biological Chemistry, Mt. Sinai School of Medicine,19–84 Annenberg Bldg., One Gustave L. Levy Pl., New York, NY 10029, USA. E-mail: lakshmi.devi{at}mssm.edu
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
opioid receptors (
OR) leads to a constitutive recruitment of ß-arrestin2 to the receptor complex resulting in changes in the spatio-temporal regulation of ERK1/2 signaling. The involvement of ß-arrestin2 is further supported by studies using ß-arrestin2 siRNA in cells endogenously expressing the heterodimers. The association of ß-arrestin2 with the heterodimer can be altered by treatment with a combination of µOR agonist (DAMGO) and
OR antagonist (Tipp
), 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-
OR heterodimers are in a conformation conducive to ß-arrestin-mediated signaling. Destabilization of this conformation by cotreatment with µOR and
OR ligands leads to a switch to a non-ß-arrestin-mediated signaling. Taken together, these results show for the first time that µOR-
OR heterodimers, by differentially recruiting ß-arrestin, modulate the spatio-temporal dynamics of opioid receptor signaling.—Rozenfeld, R., Devi, L. A. Receptor heterodimerization leads to a switch in signaling: ß-arrestin2-mediated ERK activation by µ-
opioid receptor heterodimers.
Key Words: G-protein-coupled receptors morphine oligomerization 7TM receptors enkephalin narcotic addiction
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