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δ Subunit‐containing GABA A receptors are preferred targets for the centrally acting analgesic flupirtine
Author(s) -
Klinger Felicia,
Bajric Mirnes,
Salzer Isabella,
Dorostkar Mario M.,
Khan Deeba,
Pollak Daniela D.,
Kubista Helmut,
Boehm Stefan,
Koenig Xaver
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13262
Subject(s) - chemistry , inhibitory postsynaptic potential , gabaa receptor , postsynaptic potential , agonist , receptor , neuroscience , pharmacology , biochemistry , biology
Background and Purpose The K v 7 channel activator flupirtine is a clinical analgesic characterized as ‘selective neuronal potassium channel opener’. Flupirtine was found to exert comparable actions at GABA A receptors and K v 7 channels in neurons of pain pathways, but not in hippocampus. Experimental Approach Expression patterns of GABA A 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 GABA A receptors were investigated in patch clamp experiments and compared with the actions on K v 7 channels. Key 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 K v 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 and Implications Flupirtine prefers δ‐containing GABA A receptors over γ‐containing ones and over K v 7 channels.