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Br J Pharmacol
2013 Oct 01;1704:919-32. doi: 10.1111/bph.12340.
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The orthosteric GABAA receptor ligand Thio-4-PIOL displays distinctly different functional properties at synaptic and extrasynaptic receptors.
Hoestgaard-Jensen K, O'Connor RM, Dalby NO, Simonsen C, Finger BC, Golubeva A, Hammer H, Bergmann ML, Kristiansen U, Krogsgaard-Larsen P, Bräuner-Osborne H, Ebert B, Frølund B, Cryan JF, Jensen AA.
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BACKGROUND AND PURPOSE: 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.
EXPERIMENTAL APPROACH: 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.
KEY 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.
CONCLUSION AND IMPLICATIONS: 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.
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