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    Anion-selective Cys-loop receptors (GABA and glycine receptors) provide the main inhibitory drive in the CNS. Both types of receptor operate via chloride-selective ion channels, though with different kinetics, pharmacological profiles, and localization. Disequilibrium in their function leads to a variety of disorders, which are often treated with allosteric modulators. The few available GABA and glycine receptor channel blockers effectively suppress inhibitory currents in neurons, but their systemic administration is highly toxic. With the aim of developing an efficient light-controllable modulator of GABA receptors, we constructed azobenzene-nitrazepam (Azo-NZ1), which is composed of a nitrazepam moiety merged to an azobenzene photoisomerizable group. The experiments were carried out on cultured cells expressing Cys-loop receptors of known subunit composition and in brain slices using patch-clamp. Site-directed mutagenesis and molecular modelling approaches were applied to evaluate the mechanism of action of Azo-NZ1. At visible light, being in trans-configuration, Azo-NZ1 blocked heteromeric α1/β2/γ2 GABAA receptors, ρ2 GABAA (GABAC ), and α2 glycine receptors, whereas switching the compound into cis-state by UV illumination restored the activity. Azo-NZ1 successfully photomodulated GABAergic currents recorded from dentate gyrus neurons. We demonstrated that in trans-configuration, Azo-NZ1 blocks the Cl-selective ion pore of GABA receptors interacting mainly with the 2' level of the TM2 region. Azo-NZ1 is a soluble light-driven Cl-channel blocker, which allows photo-modulation of the activity induced by anion-selective Cys-loop receptors. Azo-NZ1 is able to control GABAergic postsynaptic currents and provides new opportunities to study inhibitory neurotransmission using patterned illumination. © 2019 Institut de Neurosciences des Systémes. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.


    Galyna Maleeva, Daniel Wutz, Karin Rustler, Alba Nin-Hill, Carme Rovira, Elena Petukhova, Antoni Bautista-Barrufet, Alexandre Gomila-Juaneda, Petra Scholze, Franck Peiretti, Mercedes Alfonso-Prieto, Burkhard König, Pau Gorostiza, Piotr Bregestovski. A photoswitchable GABA receptor channel blocker. British journal of pharmacology. 2019 Aug;176(15):2661-2677

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    PMID: 30981211

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