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Analysis of functional selectivity at the nociceptin opioid receptor (1066.2)
Author(s) -
Chang Steven,
Spangler Skylar,
Zhang Nancy,
Planer William,
Carroll F,
Bruchas Michael
Publication year - 2014
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/fasebj.28.1_supplement.1066.2
Subject(s) - nociceptin receptor , functional selectivity , nop , signal transduction , receptor , chemistry , opioid receptor , microbiology and biotechnology , g protein coupled receptor , internalization , ligand (biochemistry) , opioid , opioid peptide , biochemistry , biology
The Nociceptin/Orphanin FQ Opioid Receptor (NOPR) is the most recently discovered and least characterized G‐protein coupled receptor in the opioid receptor family. The activity of NOPR has been thought to play a role in neuromodulation in the contexts of pain, opioid tolerance, and the modulation of stress and anxiety behaviors. It is thought that the NOP receptor may bind functionally selective ligands which can bias signal transduction, resulting in multiple behavioral manifestations. Functional selectivity at the NOPR has yet to be explored, but this information is integral to understanding the complex modulation of behaviors. To study the functional selectivity of NOPR, we used live‐cell cAMP assays, BRET, as well as MAP kinase activity assays to study the Gα‐protein mediated and arrestin‐mediated signaling profiles. We screened multiple known NOPR ligands and novel, small molecules aimed at elucidating structural significance. We have found that NOPR does exhibit different signaling profiles, depending on the interacting ligand. Specifically, we show that minute changes in the structure can illicit opposing signaling profiles ranging from agonism to inverse agonism. Additionally, we propose ligand‐receptor docking configurations that may help elucidate the conformational influence on functional selectivity. Additionally, we screened the same ligands in an internalization and arrestin‐recruitment deficient NOPR point mutant (Zhang et al., 2012). Interestingly, the mutation of the Serine 363 phosphorylation site shows altered signaling profiles for the same ligands in comparison to the wild‐type receptor. In addition, the signaling profiles of the novel NOPR ligands may provide new insight into the structural relationship between ligands and biased signal transduction. Taken together, these data provide novel insight into the functional selectivity of the NOP receptor, and how it affects behavioral manifestation. Supported by: NIH R00 DA025182 and T32 DA007261. Grant Funding Source : T32 DA007261