A photoswitchable GABA receptor channel blocker.

Animals Brain / drug effects CHO Cells Chloride Channels / antagonists & inhibitors Cricetulus Female GABA-A Receptor Antagonists / pharmacology Light Male Mice, Inbred ICR Models, Molecular Receptors, GABA-A / physiology

Journal

British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536

Informations de publication

Date de publication:
08 2019
Historique:
received: 24 12 2018
revised: 03 03 2019
accepted: 03 04 2019
pubmed: 14 4 2019
medline: 12 9 2020
entrez: 14 4 2019
Statut: ppublish

Résumé

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 GABA 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.

Sections du résumé

BACKGROUND AND PURPOSE
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.
EXPERIMENTAL APPROACH
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.
KEY RESULTS
At visible light, being in trans-configuration, Azo-NZ1 blocked heteromeric α1/β2/γ2 GABA
CONCLUSIONS AND IMPLICATIONS
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.

Identifiants

DOI: 10.1111/bph.14689 PMID: 30981211 PMC: PMC6609548
pubmed: 30981211
doi: 10.1111/bph.14689
pmc: PMC6609548
doi:

Substances chimiques

Chloride Channels 0
GABA-A Receptor Antagonists 0
Receptors, GABA-A 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2661-2677

Informations de copyright

© 2019 Institut de Neurosciences des Systémes. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

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Auteurs

Galyna Maleeva (G)

INSERM, INS, Institut de Neurosciences des Systèmes, Aix-Marseille University, Marseille, France.

Daniel Wutz (D)

Institute of Organic Chemistry, University of Regensburg, Regensburg, Germany.

Karin Rustler (K)

Institute of Organic Chemistry, University of Regensburg, Regensburg, Germany.
ORCID: 0000-0001-6548-1333

Alba Nin-Hill (A)

Departament de Química Inorgànica i Orgànica (Secció de Química Orgànica) and Institut de Química Teòrica i Computacional (IQTCUB), Universitat de Barcelona, Barcelona, Spain.

Carme Rovira (C)

Departament de Química Inorgànica i Orgànica (Secció de Química Orgànica) and Institut de Química Teòrica i Computacional (IQTCUB), Universitat de Barcelona, Barcelona, Spain.
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.

Elena Petukhova (E)

Department of Normal Physiology, Kazan State Medical University, Kazan, Russia.

Antoni Bautista-Barrufet (A)

Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.

Alexandre Gomila-Juaneda (A)

Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.

Petra Scholze (P)

Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University Vienna, Vienna, Austria.

Franck Peiretti (F)

INSERM 1263, INRA 1260, C2VN, Aix-Marseille Université, Marseille, France.

Mercedes Alfonso-Prieto (M)

Department of Computational Biomedicine, Institute for Advanced Simulations IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, Jülich, Germany.
Cécile and Oskar Vogt Institute for Brain Research, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
ORCID: 0000-0003-4509-4517

Burkhard König (B)

Institute of Organic Chemistry, University of Regensburg, Regensburg, Germany.

Pau Gorostiza (P)

Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
Network Biomedical Research Center in Biomaterials, Bioengineering and Nanomedicine (CIBER-BBN), Spain.
ORCID: 0000-0002-7268-5577

Piotr Bregestovski (P)

INSERM, INS, Institut de Neurosciences des Systèmes, Aix-Marseille University, Marseille, France.
Department of Normal Physiology, Kazan State Medical University, Kazan, Russia.
Institute of Neurosciences, Kazan State Medical University, Kazan, Russia.
ORCID: 0000-0003-2699-7825

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › A photoswitchable GABA receptor channel blocker.
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › A photoswitchable GABA receptor channel blocker.
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules CHO › A photoswitchable GABA receptor channel blocker.
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Canaux ioniques › Canaux chlorure › A photoswitchable GABA receptor channel blocker.
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Arvicolinae › Cricetinae › Cricetulus › A photoswitchable GABA receptor channel blocker.
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Agents neuromédiateurs › Agents GABA › Antagonistes GABA › Antagonistes du récepteur GABA-A › A photoswitchable GABA receptor channel blocker.
questionsmedicales.fr › Phénomènes physiques › Rayonnement › Rayonnement non ionisant › Lumière › A photoswitchable GABA receptor channel blocker.
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée ICR › A photoswitchable GABA receptor channel blocker.
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles moléculaires › A photoswitchable GABA receptor channel blocker.
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs aux neuromédiateurs › Récepteurs aux acides aminés › Récepteurs GABA › Récepteurs GABA-A › A photoswitchable GABA receptor channel blocker.