title: Probing α4βδ GABAA receptor heterogeneity: differential regional effects of a functionally selective α4β1δ/α4β3δ receptor agonist on tonic and phasic inhibition in rat brain.
abstract: In the present study, the orthosteric GABAA receptor (GABAAR) ligand 4,5,6,7-tetrahydroisothiazolo[5,4-c]pyridin-3-ol (Thio-THIP) was found to possess a highly interesting functional profile at recombinant human GABAARs and native rat GABAARs. Whereas Thio-THIP displayed weak antagonist activity at α1,2,5β2,3γ2S and ρ1 GABAARs and partial agonism at α6β2,3δ GABAARs expressed in Xenopus oocytes, the pronounced agonism exhibited by the compound at α4β1δ and α4β3δ GABAARs was contrasted by its negligible activity at the α4β2δ subtype. To elucidate to which extent this in vitro profile translated into functionality at native GABAARs, we assessed the effects of 100 μm Thio-THIP at synaptic and extrasynaptic receptors in principal cells of four different brain regions by slice electrophysiology. In concordance with its α6β2,3δ agonism, Thio-THIP evoked robust currents through extrasynaptic GABAARs in cerebellar granule cells. In contrast, the compound did not elicit significant currents in dentate gyrus granule cells or in striatal medium spiny neurons (MSNs), indicating predominant expression of extrasynaptic α4β2δ receptors in these cells. Interestingly, Thio-THIP evoked differential degrees of currents in ventrobasal thalamus neurons, a diversity that could arise from differential expression of extrasynaptic α4βδ subtypes in the cells. Finally, whereas 100 μm Thio-THIP did not affect the synaptic currents in ventrobasal thalamus neurons or striatal MSNs, it reduced the current amplitudes recorded from dentate gyrus granule cells, most likely by targeting perisynaptic α4βδ receptors expressed at distal dendrites of these cells. Being the first published ligand capable of discriminating between β2- and β3-containing receptor subtypes, Thio-THIP could be a valuable tool in explorations of native α4βδ GABAARs.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen OE, Denmark.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hoestgaard-Jensen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen OE, Denmark.
authors.forename: Nils Ole
authors.initials: NO
authors.lastname: Dalby
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen OE, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Krall
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen OE, Denmark.
authors.forename: Harriet
authors.initials: H
authors.lastname: Hammer
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen OE, Denmark.
authors.forename: Povl
authors.initials: P
authors.lastname: Krogsgaard-Larsen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen OE, Denmark.
authors.forename: Bente
authors.initials: B
authors.lastname: Frølund
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen OE, Denmark aaj@sund.ku.dk.
authors.forename: Anders A
authors.initials: AA
authors.lastname: Jensen
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D002531:Cerebellum / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology; D018891:Dentate Gyrus / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D058785:GABA-A Receptor Agonists / Q000494:pharmacology*; D006801:Humans; 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 / Q000502:physiology; D021122:Protein Subunits / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000187:drug effects; D013788:Thalamus / Q000187:drug effects / Q000502:physiology; D014981:Xenopus
chemical_list: C000595274:4,5,6,7-tetrahydroisoxazolo(3,4c)pyridin-5-ol; D058785:GABA-A Receptor Agonists; D007555:Isoxazoles; D021122:Protein Subunits; D011963:Receptors, GABA-A; D011994:Recombinant Proteins
keywords: GABA; GABA-A receptors; extrasynaptic; subtype-selective; tonic inhibition; α4βδ