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Pharmacological profile of nociceptin/orphanin FQ receptors interacting with G-proteins and β-arrestins 2

By D. Malfacini, C. Ambrosio, M.C. Gro', M. Sbraccia, C. Trapella, R. Guerrini, M. Bonora, P. Pinton, T. Costa and G. Calo'


Nociceptin/orphanin FQ (N/OFQ) controls several biological functions by selectively activating\ud an opioid like receptor named N/OFQ peptide receptor (NOP). Biased agonism is\ud emerging as an important and therapeutically relevant pharmacological concept in the field\ud of G protein coupled receptors including opioids. To evaluate the relevance of this phenomenon\ud in the NOP receptor, we used a bioluminescence resonance energy transfer technology\ud to measure the interactions of the NOP receptor with either G proteins or β-arrestin 2 in\ud the absence and in presence of increasing concentration of ligands. A large panel of receptor\ud ligands was investigated by comparing their ability to promote or block NOP/G protein\ud and NOP/arrestin interactions. In this study we report a systematic analysis of the functional\ud selectivity of NOP receptor ligands. NOP/G protein interactions (investigated in cell membranes)\ud allowed a precise estimation of both ligand potency and efficacy yielding data highly\ud consistent with the known pharmacological profile of this receptor. The same panel of\ud ligands displayed marked differences in the ability to promote NOP/β-arrestin 2 interactions\ud (evaluated in whole cells). In particular, full agonists displayed a general lower potency and\ud for some ligands an inverted rank order of potency was noted. Most partial agonists\ud behaved as pure competitive antagonists of receptor/arrestin interaction. Antagonists displayed\ud similar values of potency for NOP/Gβ1 or NOP/β-arrestin 2 interaction. Using N/OFQ\ud as reference ligand we computed the bias factors of NOP ligands and a number of agonists\ud with greater efficacy at G protein coupling were identified

Topics: Agricultural and Biological Sciences (all), Biochemistry, Genetics and Molecular Biology (all), Medicine (all)
Year: 2015
DOI identifier: 10.1371/journal.pone.0132865
OAI identifier: oai:iris.unife.it:11392/2333854
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