title: The dual modulation of GIRK1/GIRK2 channels by opioid receptor ligands.
abstract: It is well known that activation of the cloned kappa-opioid receptor by nanomolar concentrations of U50488H (trans-(+/-)-3, 4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl-benzeneacetamide) , a selective kappa-opioid receptor agonist, leads to the opening of GIRK1 channels. In this study, we demonstrate that the cloned kappa-opioid receptor functionally couples to GIRK1/GIRK2 channels (G-protein-coupled inwardly rectifying K(+) channels), mimicking the probable heteromultimeric state of neuronal GIRK channels. We also show that micromolar concentrations of U50488H reduce GIRK1/GIRK2 current through direct GIRK1/GIRK2 channel block in a voltage-independent manner (IC(50)=70.28+/-3.68 microM). Similarly, it was found that propoxyphene, methadone, and naloxone also can block GIRK1/GIRK2 current. In contrast, elevated concentrations of morphine (up to 1 mM) did not cause channel block. The related inwardly rectifying K(+) channel, IRK1, was not affected by elevated concentrations of these drugs. We conclude that nanomolar concentrations of opioid receptor ligands activate GIRK1/GIRK2 channels through a receptor-mediated pathway, while micromolar concentrations of some opioid receptor ligands inhibit GIRK1/GIRK2 channels by direct channel block.
authors.affiliation: Faculty of Pharmaceutical Sciences, Laboratory of Toxicology, Van Evenstraat 4, 3000, Leuven, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Ulens
authors.forename: P
authors.initials: P
authors.lastname: Daenens
authors.forename: J
authors.initials: J
authors.lastname: Tytgat
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D004274:DNA, Recombinant; D011431:Dextropropoxyphene / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D008024:Ligands; D008564:Membrane Potentials / Q000187:drug effects; D008691:Methadone / Q000494:pharmacology; D051379:Mice; D008845:Microinjections; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010957:Plasmids / Q000235:genetics; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D018075:RNA, Complementary / Q000008:administration & dosage / Q000235:genetics; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000819:agonists; D014982:Xenopus laevis
chemical_list: D000701:Analgesics, Opioid; D004274:DNA, Recombinant; D008024:Ligands; D015221:Potassium Channels; D018075:RNA, Complementary; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009270:Naloxone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; D019204:GTP-Binding Proteins; D011431:Dextropropoxyphene; D008691:Methadone