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Optopharmacology reveals a differential contribution of native GABAA receptors to dendritic and somatic inhibition using azogabazine

Mortensen, M; Huckvale, R; Pandurangan, AP; Baker, JR; Smart, TG; (2020) Optopharmacology reveals a differential contribution of native GABAA receptors to dendritic and somatic inhibition using azogabazine. Neuropharmacology , 176 , Article 108135. 10.1016/j.neuropharm.2020.108135. Green open access

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Abstract

γ-aminobutyric acid type-A receptors (GABAARs) are inhibitory ligand-gated ion channels in the brain that are crucial for controlling neuronal excitation. To explore their physiological roles in cellular and neural network activity, it is important to understand why specific GABAAR isoforms are distributed not only to various brain regions and cell types, but also to specific areas of the membrane in individual neurons. To address this aim we have developed a novel photosensitive compound, azogabazine, that targets and reversibly inhibits GABAARs. The receptor selectivity of the compound is based on the competitive antagonist, gabazine, and photosensitivity is conferred by a photoisomerisable azobenzene group. Azogabazine can exist in either cis or trans conformations that are controlled by UV and blue light respectively, to affect receptor inhibition. We report that the trans-isomer preferentially binds and inhibits GABAAR function, whilst promotion of the cis-isomer caused unbinding of azogabazine from GABAARs. Using cultured cerebellar granule cells, azogabazine in conjunction with UV light applied to defined membrane domains, revealed higher densities of GABAARs at somatic inhibitory synapses compared to those populating proximal dendritic zones, even though the latter displayed a higher number of synapses per unit area of membrane. Azogabazine also revealed more pronounced GABA-mediated inhibition of action potential firing in proximal dendrites compared to the soma. Overall, azogabazine is a valuable addition to the photochemical toolkit that can be used to interrogate GABAAR function and inhibition.

Type: Article
Title: Optopharmacology reveals a differential contribution of native GABAA receptors to dendritic and somatic inhibition using azogabazine
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.neuropharm.2020.108135
Publisher version: https://doi.org/10.1016/j.neuropharm.2020.108135
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: GABAA receptor, synaptic inhibition, azobenzene, optopharmacology, photoisomerization, gabazine, azogabazine, GABA, homology modelling, computational ligand docking, cerebellar granule neurons.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10099726
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