Journal Article

FZJ-2019-04249

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A photoswitchable GABA receptor channel blocker

Maleeva, G.AMU* ; Wutz, D. ; Rustler, K. ; Nin‐Hill, A. ; Petukhova, E. ; Bautista‐Barrufet, A. ; Gomila‐Juaneda, A. ; Scholze, P. ; Peiretti, F.AMU* ; Rovira, C. ; König, B. ; Gorostiza, P. (Corresponding author) ; Bregestovski, P. (Corresponding author)AMU* ; Alfonso-Prieto, M. (Corresponding author)FZJ*

2019
Wiley Malden, MA

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Please use a persistent id in citations: http://hdl.handle.net/2128/22868  doi:10.1111/bph.14689

Abstract: Background and PurposeAnion‐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.Experimental ApproachThe 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.Key ResultsAt 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.Conclusions and ImplicationsAzo‐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.

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Contributing Institute(s):

1. Computational Biomedicine (IAS-5)
2. Computational Biomedicine (INM-9)

Research Program(s):

1. 571 - Connectivity and Activity (POF3-571) (POF3-571)
2. 574 - Theory, modelling and simulation (POF3-574) (POF3-574)

Appears in the scientific report 2019

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