Agonist-specific recruitment of arrestin isoforms differentially modify delta opioid receptor function

Amynah A. Pradhan, Julie Perroy, Wendy M. Walwyn, Monique L. Smith, Ana Vicente-Sanchez, Laura Segura, Alia Bana, Brigitte L. Kieffer, Christopher J. Evans

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


Ligand-specific recruitment of arrestins facilitates functional selectivity of G-protein-coupled receptor signaling. Here, we describe agonist-selective recruitment of different arrestin isoforms to the delta opioid receptor inmice. Ahigh-internalizing delta opioid receptor agonist (SNC80) preferentially recruited arrestin 2 and, in arrestin 2 knock-outs (KOs), we observed a significant increase in the potency of SNC80 to inhibit mechanical hyperalgesia and decreased acute tolerance. In contrast, the low-internalizing delta agonists (ARM390, JNJ20788560) preferentially recruited arrestin 3 with unaltered behavioral effects in arrestin 2 KOs. Surprisingly, arrestin 3 KO revealed an acute tolerance to these low-internalizing agonists, an effect never observed in wild-type animals. Furthermore, we examined delta opioid receptor–Ca2+ channel coupling in dorsal root ganglia desensitized by ARM390 and the rate of resensitization was correspondingly decreased in arrestin 3 KOs. Live-cell imaging in HEK293 cells revealed that delta opioid receptors are in pre-engaged complexes with arrestin 3 at the cell membrane and that ARM390 strengthens this membrane interaction. The disruption of these complexes in arrestin 3 KOs likely accounts for the altered responses to low-internalizing agonists. Together, our results show agonist-selective recruitment of arrestin isoforms and reveal a novel endogenous role of arrestin 3 as a facilitator of resensitization and an inhibitor of tolerance mechanisms.

Original languageEnglish
Pages (from-to)3541-3551
Number of pages11
JournalJournal of Neuroscience
Issue number12
StatePublished - Mar 23 2016


  • Arrestin
  • DRG
  • GPCR
  • Pain
  • Resensitization
  • Tolerance


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