Modulation of silent and constitutively active nociceptin/orphanin FQ receptors by potent receptor antagonists and Na+ Ions in rat sympathetic neurons

Saifeldin Mahmoud, Wojciech Margas, Claudio Trapella, Girolamo Caló, Victor Ruiz-Velasco

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21 Scopus citations


The pharmacology of G protein-coupled receptors can be influenced by factors such as constitutive receptor activation and Na+ ions. In this study, we examined the coupling of natively and heterologously expressed nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptors with voltage-dependent Ca2+ channels after exposure to four high-affinity NOP receptor blockers [[Nphe1Arg14Lys15]N/OFQ-NH2 (UFP-101), 1-[1-(cyclooctylmethyl)-1,2,3,6-tetrahydro-5-(hydroxymethyl)-4- pyridinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (Trap-101), 1-benzyl-N-{3-[spiroisobenzofuran-1(3H),4′-piperidin-1-yl]propyl} pyrrolidine-2-carboxamide (compound 24), and N-(4-amino-2-methylquinolin-6-yl)- 2-(4-ethylphenoxymethyl) benzamide hydrochloride (JTC-801)] in sympathetic neurons. The enhanced tonic inhibition of Ca2+ currents in the absence of agonists, indicative of constitutively active NOP receptors in transfected neurons, was abolished after pretreatment with pertussis toxin. In control neurons, the four antagonists did not exert any effects when applied alone but significantly blocked the N/OFQ-mediated Ca2+ current inhibition. Exposure of transfected neurons to UFP-101 resulted in partial agonist effects. In contrast, Trap-101, compound 24, and JTC-801 exerted inverse agonism, as measured by the loss of tonic Ca2+ current inhibition. In experiments designed to measure the N/OFQ concentrationresponse relationship under varying Na+ concentrations, a leftward shift of IC50 values was observed after Na+ exposure. Although similar N/OFQ efficacies were measured with all solutions, a significant decrease of Hill coefficient values was obtained with increasing Na+ concentrations. Examination of the allosteric effects of Na+ on heterologously overexpressed NOP receptors showed that the tonic Ca2+ current inhibition was abolished in the presence of the monovalent cation. These results demonstrate that constitutively active NOP receptors exhibit differential blocker pharmacology and allosteric regulation by Na+. Data are also presented demonstrating that heterologously expressed μ opioid receptors in sympathetic neurons are similarly modulated.

Original languageEnglish (US)
Pages (from-to)804-817
Number of pages14
JournalMolecular pharmacology
Issue number5
StatePublished - May 2010

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology


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