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@ARTICLE{Maleeva:864468,
      author       = {Maleeva, Galyna and Wutz, Daniel and Rustler, Karin and
                      Nin‐Hill, Alba and Petukhova, Elena and
                      Bautista‐Barrufet, Antoni and Gomila‐Juaneda, Alexandre
                      and Scholze, Petra and Peiretti, Franck and Rovira, Carme
                      and König, Burkhard and Gorostiza, Pau and Bregestovski,
                      Piotr and Alfonso-Prieto, Mercedes},
      title        = {{A} photoswitchable {GABA} receptor channel blocker},
      journal      = {British journal of pharmacology},
      volume       = {176},
      number       = {15},
      issn         = {1476-5381},
      address      = {Malden, MA},
      publisher    = {Wiley},
      reportid     = {FZJ-2019-04249},
      pages        = {2661-2677},
      year         = {2019},
      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.},
      cin          = {IAS-5 / INM-9},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121},
      pnm          = {571 - Connectivity and Activity (POF3-571) / 574 - Theory,
                      modelling and simulation (POF3-574)},
      pid          = {G:(DE-HGF)POF3-571 / G:(DE-HGF)POF3-574},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30981211},
      UT           = {WOS:000474034600001},
      doi          = {10.1111/bph.14689},
      url          = {https://juser.fz-juelich.de/record/864468},
}