title: Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABAA receptors.
abstract: The activation characteristics of synaptic and extrasynaptic GABA(A) receptors are important for shaping the profile of phasic and tonic inhibition in the central nervous system, which will critically impact on the activity of neuronal networks. Here, we study in isolation the activity of three agonists, GABA, muscimol and 4,5,6,7-tetrahydoisoxazolo[5,4-c]pyridin-3(2H)-one (THIP), to further understand the activation profiles of alpha 1 beta 3 gamma 2, alpha 4 beta 3 gamma 2 and alpha 4 beta 3 delta receptors that typify synaptic- and extrasynaptic-type receptors expressed in the hippocampus and thalamus. The agonists display an order of potency that is invariant between the three receptors, which is reliant mostly on the agonist dissociation constant. At delta subunit-containing extrasynaptic-type GABA(A) receptors, both THIP and muscimol additionally exhibited, to different degrees, superagonist behaviour. By comparing whole-cell and single channel currents induced by the agonists, we provide a molecular explanation for their different activation profiles. For THIP at high concentrations, the unusual superagonist behaviour on alpha 4 beta 3 delta receptors is a consequence of its ability to increase the duration of longer channel openings and their frequency, resulting in longer burst durations. By contrast, for muscimol, moderate superagonist behaviour was caused by reduced desensitisation of the extrasynaptic-type receptors. The ability to specifically increase the efficacy of receptor activation, by selected exogenous agonists over that obtained with the natural transmitter, may prove to be of therapeutic benefit under circumstances when synaptic inhibition is compromised or dysfunctional.
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Mortensen
authors.forename: Bjarke
authors.initials: B
authors.lastname: Ebert
authors.forename: Keith
authors.initials: K
authors.lastname: Wafford
authors.forename: Trevor G
authors.initials: TG
authors.lastname: Smart
mesh_terms: D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D018755:GABA Agonists / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007555:Isoxazoles / Q000494:pharmacology; D007668:Kidney / Q000166:cytology / Q000187:drug effects; D051379:Mice; D009118:Muscimol / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D018755:GABA Agonists; D007555:Isoxazoles; D011963:Receptors, GABA-A; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; C015542:gaboxadol