Journal
JOURNAL OF NEUROSCIENCE
Volume 36, Issue 12, Pages 3541-3551Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4124-15.2016
Keywords
arrestin; DRG; GPCR; pain; resensitization; tolerance
Categories
Funding
- National Institute on Drug Abuse-National Institutes of Health [DA05010, DA031243]
- European Research Council under the European Union's Horizon Research and Innovation Programme [646788]
- Agence Nationale de la Recherche [ANR-13-JSV4-0005-01]
- Shirley and Stefan Hatos Research Foundation
- Department of Psychiatry at University of Illinois-Chicago (UIC)
- European Research Council (ERC) [646788] Funding Source: European Research Council (ERC)
- Agence Nationale de la Recherche (ANR) [ANR-13-JSV4-0005] Funding Source: Agence Nationale de la Recherche (ANR)
Ask authors/readers for more resources
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 in mice. 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available