Receptor heterodimerization leads to a switch in signaling: beta-arrestin2-mediated ERK activation by mu-delta 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 (muOR), is of great clinical relevance. Here we show that heterodimerization of muOR with delta opioid receptors (deltaOR) leads to a constitutive recruitment of beta-arrestin2 to the receptor complex resulting in changes in the spatio-temporal 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-arrestin2 with the heterodimer can be altered by treatment with a combination of muOR agonist (DAMGO) and deltaOR antagonist (Tipp(psi)), and this leads to a shift in the pattern of ERK1/2 phosphorylation to the pattern observed with muOR alone. These data indicate that, in the naive state, muOR-deltaOR heterodimers are in a conformation conducive to beta-arrestin-mediated signaling. Destabilization of this conformation by cotreatment with muOR and deltaOR ligands leads to a switch to a non-beta-arrestin-mediated signaling. Taken together, these results show for the first time that muOR-deltaOR heterodimers, by differentially recruiting beta-arrestin, modulate the spatio-temporal dynamics of opioid receptor signaling.
Rozenfeld
Raphael
R
Department of Pharmacology and Biological Chemistry, Mt. Sinai School of Medicine, One Gustave L. Levy Pl., New York, NY 10029, USA.
Devi
Lakshmi A
LA
D000818:Animals; D019390:Arrestins / Q000502:physiology*; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D019281:Dimerization; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D007668:Kidney; D017465:Receptors, Opioid, delta / Q000235:genetics / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D000071557:beta-Arrestins
D019390:Arrestins; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D011994:Recombinant Proteins; D000071557:beta-Arrestins; D048049:Extracellular Signal-Regulated MAP Kinases