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Receptor heterodimerization leads to a switch in signaling: β‐arrestin2‐mediated ERK activation by μ‐δ opioid receptor heterodimers
Author(s) -
Rozenfeld Raphael,
Devi Lakshmi A.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-7793com
Subject(s) - arrestin , damgo , receptor , microbiology and biotechnology , signal transduction , μ opioid receptor , enkephalin , enzyme linked receptor , opioid receptor , δ opioid receptor , agonist , chemistry , g protein coupled receptor , functional selectivity , opioid , phosphorylation , neuroscience , pharmacology , biology , biochemistry
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 het‐erodimerization 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 involve‐ment 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 (Tipp Ψ ), 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.—Rozenfeld, R., Devi, L. A. Receptor heterodimerization leads to a switch in signaling: β‐ar‐restin2‐mediated ERK activation by μ‐δ opioid receptor heterodimers. FASEB J. 21, 2455–2465 (2007)