title: The orthosteric GABAA receptor ligand Thio-4-PIOL displays distinctly different functional properties at synaptic and extrasynaptic receptors.
abstract: OBJECTIVE
  Explorations into the heterogeneous population of native GABA type A receptors (GABAA Rs) and the physiological functions governed by the multiple GABAA R subtypes have for decades been hampered by the lack of subtype-selective ligands.
  
  
  METHODS
  The functional properties of the orthosteric GABAA receptor ligand 5-(4-piperidyl)-3-isothiazolol (Thio-4-PIOL) have been investigated in vitro, ex vivo and in vivo.
  
  
  RESULTS
  Thio-4-PIOL displayed substantial partial agonist activity at the human extrasynaptic GABAA R subtypes expressed in Xenopus oocytes, eliciting maximal responses of up to ∼30% of that of GABA at α5 β3 γ2S , α4 β3 δ and α6 β3 δ and somewhat lower efficacies at the corresponding α5 β2 γ2S , α4 β2 δ and α6 β2 δ subtypes (maximal responses of 4-12%). In contrast, it was an extremely low efficacious agonist at the α1 β3 γ2S , α1 β2 γ2S , α2 β2 γ2S , α2 β3 γ2S , α3 β2 γ2S and α3 β3 γ2S GABAA Rs (maximal responses of 0-4%). In concordance with its agonism at extrasynaptic GABAA Rs and its de facto antagonism at the synaptic receptors, Thio-4-PIOL elicited robust tonic currents in electrophysiological recordings on slices from rat CA1 hippocampus and ventrobasal thalamus and antagonized phasic currents in hippocampal neurons. Finally, the observed effects of Thio-4-PIOL in rat tests of anxiety, locomotion, nociception and spatial memory were overall in good agreement with its in vitro and ex vivo properties.
  
  
  CONCLUSIONS
  The diverse signalling characteristics of Thio-4-PIOL at GABAA Rs represent one of the few examples of a functionally subtype-selective orthosteric GABAA R ligand reported to date. We propose that Thio-4-PIOL could be a useful pharmacological tool in future studies exploring the physiological roles of native synaptic and extrasynaptic GABAA Rs.
authors: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: K
authors: K
authors: Hoestgaard-Jensen
authors: R M
authors: RM
authors: O'Connor
authors: N O
authors: NO
authors: Dalby
authors: C
authors: C
authors: Simonsen
authors: B C
authors: BC
authors: Finger
authors: A
authors: A
authors: Golubeva
authors: H
authors: H
authors: Hammer
authors: M L
authors: ML
authors: Bergmann
authors: U
authors: U
authors: Kristiansen
authors: P
authors: P
authors: Krogsgaard-Larsen
authors: H
authors: H
authors: Bräuner-Osborne
authors: B
authors: B
authors: Ebert
authors: B
authors: B
authors: Frølund
authors: J F
authors: JF
authors: Cryan
authors: A A
authors: AA
authors: Jensen
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D054333:Drug Partial Agonism; D058785:GABA-A Receptor Agonists / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008297:Male; D008564:Membrane Potentials; D008568:Memory / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D059225:Nociception / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D014982:Xenopus laevis
chemical_list: C000590775:5-(4-piperidyl)-3-isothiazolol; D058785:GABA-A Receptor Agonists; D008024:Ligands; D010880:Piperidines; D018079:Receptors, GABA; D013844:Thiazoles
keywords: GABA; GABAA receptors; Thio-4-PIOL; functional selectivity; orthosteric ligand; partial agonism; phasic currents; subtype selectivity; tonic currents; tonic inhibition
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