title: Benzodiazepine receptor agonists affect both binding and gating of recombinant alpha1beta2gamma2 gamma-aminobutyric acid-A receptors.
abstract: Benzodiazepines are known to act by enhancing the effect of gamma-aminobutyric acid-A receptor agonists. Positive modulation by benzodiazepines is typically ascribed to upregulation of agonist binding affinity but their effect on gamma-aminobutyric acid-A receptor gating remain unclear. In this work, we have used the ultrafast application system to examine the impact of flurazepam and zolpidem on recombinant alpha1beta2gamma2 gamma-aminobutyric acid-A receptors. As expected, both drugs strongly enhanced currents evoked by low [gamma-aminobutyric acid]. These compounds, however, also affected currents elicited by saturating agonist concentration. In particular, flurazepam and zolpidem reduced current amplitudes and slowed down the recovery process in paired-pulse experiments. Moreover, flurazepam accelerated the current rise time and zolpidem enhanced the rate and extent of desensitization. We propose that flurazepam and zolpidem modulate gamma-aminobutyric acid-A receptors by strong enhancement of agonist binding with a superimposed limited effect on the receptor gating.
authors.affiliation: Laboratory of Neuroscience, Department of Biophysics, Wrocław Medical University, Wrocław, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Mercik
authors.forename: Michał
authors.initials: M
authors.lastname: Piast
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Mozrzymas
mesh_terms: D000494:Allosteric Regulation; D001665:Binding Sites / Q000187:drug effects; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D005479:Flurazepam / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques / Q000379:methods; D011725:Pyridines / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection / Q000379:methods; D000077334:Zolpidem; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D058785:GABA-A Receptor Agonists; D011725:Pyridines; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D005680:gamma-Aminobutyric Acid; D000077334:Zolpidem; D005479:Flurazepam