title: δ Subunit-containing GABAA receptors are preferred targets for the centrally acting analgesic flupirtine.
abstract: OBJECTIVE
  The Kv 7 channel activator flupirtine is a clinical analgesic characterized as 'selective neuronal potassium channel opener'. Flupirtine was found to exert comparable actions at GABAA receptors and Kv 7 channels in neurons of pain pathways, but not in hippocampus.
  
  
  METHODS
  Expression patterns of GABAA receptors were explored in immunoblots of rat dorsal root ganglia, dorsal horns and hippocampi using antibodies for 10 different subunits. Effects of flupirtine on recombinant and native GABAA receptors were investigated in patch clamp experiments and compared with the actions on Kv 7 channels.
  
  
  RESULTS
  Immunoblots pointed towards α2, α3, β3 and γ2 subunits as targets, but in all γ2-containing receptors the effects of flupirtine were alike: leftward shift of GABA concentration-response curves and diminished maximal amplitudes. After replacement of γ2S by δ, flupirtine increased maximal amplitudes. Currents through α1β2δ receptors were more enhanced than those through Kv 7 channels. In hippocampal neurons, flupirtine prolonged inhibitory postsynaptic currents, left miniature inhibitory postsynaptic currents (mIPSCs) unaltered and increased bicuculline-sensitive tonic currents; penicillin abolished mIPSCs, but not tonic currents; concentration-response curves for GABA-induced currents were shifted to the left by flupirtine without changes in maximal amplitudes; in the presence of penicillin, maximal amplitudes were increased; GABA-induced currents in the presence of penicillin were more sensitive towards flupirtine than K(+) currents. In dorsal horn neurons, currents evoked by the δ-preferring agonist THIP (gaboxadol) were more sensitive towards flupirtine than K(+) currents.
  
  
  CONCLUSIONS
  Flupirtine prefers δ-containing GABAA receptors over γ-containing ones and over Kv 7 channels.
authors.affiliation: Department of Neurophysiology and Neuropharmacology, Centre for Physiology and Pharmacology, Medical University of Vienna, Spitalgasse 23, Vienna, 1090, Austria.
authors.forename: Felicia
authors.initials: F
authors.lastname: Klinger
authors.affiliation: Department of Neurophysiology and Neuropharmacology, Centre for Physiology and Pharmacology, Medical University of Vienna, Spitalgasse 23, Vienna, 1090, Austria.
authors.forename: Mirnes
authors.initials: M
authors.lastname: Bajric
authors.affiliation: Department of Neurophysiology and Neuropharmacology, Centre for Physiology and Pharmacology, Medical University of Vienna, Spitalgasse 23, Vienna, 1090, Austria.
authors.forename: Isabella
authors.initials: I
authors.lastname: Salzer
authors.affiliation: Department of Neurophysiology and Neuropharmacology, Centre for Physiology and Pharmacology, Medical University of Vienna, Spitalgasse 23, Vienna, 1090, Austria.
authors.forename: Mario M
authors.initials: MM
authors.lastname: Dorostkar
authors.affiliation: Department of Neurophysiology and Neuropharmacology, Centre for Physiology and Pharmacology, Medical University of Vienna, Spitalgasse 23, Vienna, 1090, Austria.
authors.forename: Deeba
authors.initials: D
authors.lastname: Khan
authors.affiliation: Department of Neurophysiology and Neuropharmacology, Centre for Physiology and Pharmacology, Medical University of Vienna, Spitalgasse 23, Vienna, 1090, Austria.
authors.forename: Daniela D
authors.initials: DD
authors.lastname: Pollak
authors.affiliation: Department of Neurophysiology and Neuropharmacology, Centre for Physiology and Pharmacology, Medical University of Vienna, Spitalgasse 23, Vienna, 1090, Austria.
authors.forename: Helmut
authors.initials: H
authors.lastname: Kubista
authors.affiliation: Department of Neurophysiology and Neuropharmacology, Centre for Physiology and Pharmacology, Medical University of Vienna, Spitalgasse 23, Vienna, 1090, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Boehm
authors.affiliation: Department of Neurophysiology and Neuropharmacology, Centre for Physiology and Pharmacology, Medical University of Vienna, Spitalgasse 23, Vienna, 1090, Austria.
authors.forename: Xaver
authors.initials: X
authors.lastname: Koenig
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D051656:KCNQ Potassium Channels / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism / Q000502:physiology*; D066148:Spinal Cord Dorsal Horn / Q000166:cytology
chemical_list: D000631:Aminopyridines; D000700:Analgesics; D051656:KCNQ Potassium Channels; D011963:Receptors, GABA-A; C034161:flupirtine