title: The GABAA antagonist DPP-4-PIOL selectively antagonises tonic over phasic GABAergic currents in dentate gyrus granule cells.
abstract: GABAA receptors mediate two different types of inhibitory currents: phasic inhibitory currents when rapid and brief presynaptic GABA release activates postsynaptic GABAA receptors and tonic inhibitory currents generated by low extrasynaptic GABA levels, persistently activating extrasynaptic GABAA receptors. The two inhibitory current types are mediated by different subpopulations of GABAA receptors with diverse pharmacological profiles. Selective antagonism of tonic currents is of special interest as excessive tonic inhibition post-stroke has severe pathological consequences. Here we demonstrate that phasic and tonic GABAA receptor currents can be selectively inhibited by the antagonists SR 95531 and the 4-PIOL derivative, 4-(3,3-diphenylpropyl)-5-(4-piperidyl)-3-isoxazolol hydrobromide (DPP-4-PIOL), respectively. In dentate gyrus granule cells, SR 95531 was found approximately 4 times as potent inhibiting phasic currents compared to tonic currents (IC50 values: 101 vs. 427 nM). Conversely, DPP-4-PIOL was estimated to be more than 20 times as potent inhibiting tonic current compared to phasic current (IC50 values: 0.87 vs. 21.3 nM). Consequently, we were able to impose a pronounced reduction in tonic GABA mediated current (>70 %) by concentrations of DPP-4-PIOL, at which no significant effect on the phasic current was seen. Our findings demonstrate that selective inhibition of GABA mediated tonic current is possible, when targeting a subpopulation of GABAA receptors located extrasynaptically using the antagonist, DPP-4-PIOL.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark.
authors.forename: Kim
authors.initials: K
authors.lastname: Boddum
authors.forename: Bente
authors.initials: B
authors.lastname: Frølund
authors.forename: Uffe
authors.initials: U
authors.lastname: Kristiansen
mesh_terms: D000818:Animals; D003594:Cytoplasmic Granules / Q000187:drug effects* / Q000378:metabolism; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D058787:GABA-A Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000187:drug effects
chemical_list: D058787:GABA-A Receptor Antagonists; D007555:Isoxazoles; D010880:Piperidines; D011963:Receptors, GABA-A; C073009:5-(4-piperidyl)isoxazol-3-ol; D005680:gamma-Aminobutyric Acid
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