title: Context-Dependent Modulation of GABAAR-Mediated Tonic Currents.
abstract: Tonic GABA currents mediated by high-affinity extrasynaptic GABAA receptors, are increasingly recognized as important regulators of cell and neuronal network excitability. Dysfunctional GABAA receptor signaling that results in modified tonic GABA currents is associated with a number of neurological disorders. Consequently, developing compounds to selectively modulate the activity of extrasynaptic GABAA receptors underlying tonic inhibition is likely to prove therapeutically useful. Here, we examine the GABAA receptor subtype selectivity of the weak partial agonist, 5-(4-piperidyl)isoxazol-3-ol (4-PIOL), as a potential mechanism for modulating extrasynaptic GABAA receptor-mediated tonic currents. By using recombinant GABAA receptors expressed in HEK293 cells, and native GABAA receptors of cerebellar granule cells, hippocampal neurons, and thalamic relay neurons, 4-PIOL evidently displayed differential agonist and antagonist-type profiles, depending on the extrasynaptic GABAA receptor isoforms targeted. For neurons, this resulted in differential modulation of GABA tonic currents, depending on the cell type studied, their respective GABAA receptor subunit compositions, and critically, on the ambient GABA levels. Unexpectedly, 4-PIOL revealed a significant population of relatively low-affinity γ2 subunit-containing GABAA receptors in the thalamus, which can contribute to tonic inhibition under specific conditions when GABA levels are raised. Together, these data indicate that partial agonists, such as 4-PIOL, may be useful for modulating GABAA receptor-mediated tonic currents, but the direction and extent of this modulation is strongly dependent on relative expression levels of different extrasynaptic GABAA receptor subtypes, and on the ambient GABA levels.
  
  
  CONCLUSIONS
  A background level of inhibition (tonic) is important in the brain for controlling neuronal excitability. Increased levels of tonic inhibition are associated with some neurological disorders but there are no specific ligands capable of selectively reducing tonic inhibition. Here we explore the use of a GABA partial agonist as a selective chemical tool in three different brain regions. We discover that the activity of a partial agonist is heavily dependent upon the GABAA receptor subunit composition underpinning tonic inhibition, and on the ambient levels of GABA in the brain.
authors.affiliation: Department of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, United Kingdom, and.
authors.forename: Bijal
authors.initials: B
authors.lastname: Patel
authors.affiliation: Department of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, United Kingdom, and.
authors.forename: Damian P
authors.initials: DP
authors.lastname: Bright
authors.affiliation: Department of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, United Kingdom, and.
authors.forename: Martin
authors.initials: M
authors.lastname: Mortensen
authors.affiliation: Faculty of Health and Medical Sciences, Medicinal Chemistry Research, University of Copenhagen, Jagtvej 162, 2100 Copenhagen Ø, Denmark.
authors.forename: Bente
authors.initials: B
authors.lastname: Frølund
authors.affiliation: Department of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, United Kingdom, and t.smart@ucl.ac.uk.
authors.forename: Trevor G
authors.initials: TG
authors.lastname: Smart
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D018682:GABA Agents / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007555:Isoxazoles / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D018683:Excitatory Amino Acid Agents; D018682:GABA Agents; D007555:Isoxazoles; D010880:Piperidines; D021122:Protein Subunits; D011963:Receptors, GABA-A; C073009:5-(4-piperidyl)isoxazol-3-ol; D005680:gamma-Aminobutyric Acid
keywords: 4-PIOL; GABA; extrasynaptic GABA receptors; partial agonist; synaptic inhibition; tonic inhibition