Agonist-Specific Recruitment of Arrestin Isoforms Differentially Modify Delta Opioid Receptor Function.
|Title||Agonist-Specific Recruitment of Arrestin Isoforms Differentially Modify Delta Opioid Receptor Function.|
|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||Pradhan AA, Perroy J, Walwyn WM, Smith ML, Vicente-Sanchez A, Segura L, Bana A, Kieffer BL, Evans CJ|
|Date Published||2016 Mar 23|
|Keywords||Animals, Arrestins, Benzamides, Drug Tolerance, Female, Hyperalgesia, Male, Mice, Mice, Knockout, Pain Perception, Piperazines, Protein Isoforms, Receptors, Opioid, delta|
UNLABELLED: 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. A high-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-Ca(2+)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.SIGNIFICANCE STATEMENT: Agonists that bind to the same receptor can produce highly distinct signaling events and arrestins are a major mediator of this ligand bias. Here, we demonstrate that delta opioid receptor agonists differentially recruit arrestin isoforms. We found that the high-internalizing agonist SNC80 preferentially recruits arrestin 2 and knock-out (KO) of this protein results in increased efficacy of SNC80. In contrast, low-internalizing agonists (ARM390 and JNJ20788560) preferentially recruit arrestin 3 and, surprisingly, KO of arrestin 3 produces acute tolerance and impaired receptor resensitization to these agonists. Arrestin 3 is in pre-engaged complexes with the delta opioid receptor at the cell membrane and low-internalizing agonists promote this interaction. This study reveals a novel role for arrestin 3 as a facilitator of receptor resensitization.
|Alternate Journal||J. Neurosci.|
|PubMed Central ID||PMC4804011|
|Grant List||P50 DA005010 / DA / NIDA NIH HHS / United States |
DA031243 / DA / NIDA NIH HHS / United States
R00 DA031243 / DA / NIDA NIH HHS / United States
DA05010 / DA / NIDA NIH HHS / United States
K99 DA031243 / DA / NIDA NIH HHS / United States