Quercetin antagonism of GABAAρ1 receptors is prevented by ascorbic acid through a redox-independent mechanism
Quercetin is a natural flavonoid widely distributed in plants that acts as a neuroprotective agent and modulates the activity of different synaptic receptors and ion channels, including the ionotropic GABA receptors. GABA Aρ1 receptors were shown to be antagonized by quercetin, but the mechanisms un...
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2013
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00142999_v714_n1-3_p274_Calero http://hdl.handle.net/20.500.12110/paper_00142999_v714_n1-3_p274_Calero |
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paper:paper_00142999_v714_n1-3_p274_Calero2023-06-08T14:36:55Z Quercetin antagonism of GABAAρ1 receptors is prevented by ascorbic acid through a redox-independent mechanism Calero, Cecilia Inés Calvo, Daniel Juan Allosteric modulator Ascorbic acid Flavonoid GABA receptor Quercetin 4 aminobutyric acid 4 aminobutyric acid A receptor 4 aminobutyric acid A receptor blocking agent 4 aminobutyric acid receptor ascorbic acid flavonoid histidine quercetin 4 aminobutyric acid A receptor 4 aminobutyric acid A receptor blocking agent ascorbic acid quercetin γ-aminobutyric acid Allosteric modulator allosterism animal article chemistry dose response drug antagonism drug effect human metabolism N-ethylmaleimide NEM antagonists and inhibitors drug effects γ-aminobutyric acid Allosteric modulator Ascorbic acid Flavonoid GABA GABA receptor N-ethylmaleimide NEM Quercetin Allosteric Regulation Animals Ascorbic Acid Dose-Response Relationship, Drug GABA-A Receptor Antagonists Histidine Humans Quercetin Receptors, GABA-A Allosteric Regulation Animals Ascorbic Acid Dose-Response Relationship, Drug GABA-A Receptor Antagonists Histidine Humans Quercetin Receptors, GABA-A Quercetin is a natural flavonoid widely distributed in plants that acts as a neuroprotective agent and modulates the activity of different synaptic receptors and ion channels, including the ionotropic GABA receptors. GABA Aρ1 receptors were shown to be antagonized by quercetin, but the mechanisms underlying these antagonistic actions are still unknown. We have analyzed here if the antagonistic action produced by quercetin on GABA Aρ1 receptors was related to its redox activity or due to alternative mechanism/s. Homomeric GABAAρ1 receptors were expressed in frog oocytes and GABA-evoked responses electro-physiologically recorded. Quercetin effects on GABAAρ1 receptors were examined in the absence or presence of ascorbic acid. Chemical protection of cysteines by selective sulfhydryl reagents and site directed mutagenesis experiments were also used to determine ρ1 subunit residues involved in quercetin actions. Quercetin antagonized GABAAρ1 receptor responses in a dose-dependent, fast and reversible manner. Quercetin inhibition was prevented in the presence of ascorbic acid, but not by thiol reagents that modify the extracellular Cys-loop of these receptors. H141, an aminoacidic residue located near to the ρ1 subunit GABA binding site, was involved in the allosteric modulation of GABAAρ1 receptors by several agents including ascorbic acid. Quercetin similarly antagonized GABA-evoked responses mediated by mutant H141DGABAAρ1 and wild-type receptors, but prevention exerted by ascorbic acid on quercetin effects was impaired in mutant receptors. Taken together the present results suggest that quercetin antagonistic actions on GABAAρ1 receptors are mediated through a redox-independent allosteric mechanism. © 2013 Elsevier B.V. All rights reserved. Fil:Calero, C.I. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Calvo, D.J. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2013 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00142999_v714_n1-3_p274_Calero http://hdl.handle.net/20.500.12110/paper_00142999_v714_n1-3_p274_Calero |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Allosteric modulator Ascorbic acid Flavonoid GABA receptor Quercetin 4 aminobutyric acid 4 aminobutyric acid A receptor 4 aminobutyric acid A receptor blocking agent 4 aminobutyric acid receptor ascorbic acid flavonoid histidine quercetin 4 aminobutyric acid A receptor 4 aminobutyric acid A receptor blocking agent ascorbic acid quercetin γ-aminobutyric acid Allosteric modulator allosterism animal article chemistry dose response drug antagonism drug effect human metabolism N-ethylmaleimide NEM antagonists and inhibitors drug effects γ-aminobutyric acid Allosteric modulator Ascorbic acid Flavonoid GABA GABA receptor N-ethylmaleimide NEM Quercetin Allosteric Regulation Animals Ascorbic Acid Dose-Response Relationship, Drug GABA-A Receptor Antagonists Histidine Humans Quercetin Receptors, GABA-A Allosteric Regulation Animals Ascorbic Acid Dose-Response Relationship, Drug GABA-A Receptor Antagonists Histidine Humans Quercetin Receptors, GABA-A |
| spellingShingle |
Allosteric modulator Ascorbic acid Flavonoid GABA receptor Quercetin 4 aminobutyric acid 4 aminobutyric acid A receptor 4 aminobutyric acid A receptor blocking agent 4 aminobutyric acid receptor ascorbic acid flavonoid histidine quercetin 4 aminobutyric acid A receptor 4 aminobutyric acid A receptor blocking agent ascorbic acid quercetin γ-aminobutyric acid Allosteric modulator allosterism animal article chemistry dose response drug antagonism drug effect human metabolism N-ethylmaleimide NEM antagonists and inhibitors drug effects γ-aminobutyric acid Allosteric modulator Ascorbic acid Flavonoid GABA GABA receptor N-ethylmaleimide NEM Quercetin Allosteric Regulation Animals Ascorbic Acid Dose-Response Relationship, Drug GABA-A Receptor Antagonists Histidine Humans Quercetin Receptors, GABA-A Allosteric Regulation Animals Ascorbic Acid Dose-Response Relationship, Drug GABA-A Receptor Antagonists Histidine Humans Quercetin Receptors, GABA-A Calero, Cecilia Inés Calvo, Daniel Juan Quercetin antagonism of GABAAρ1 receptors is prevented by ascorbic acid through a redox-independent mechanism |
| topic_facet |
Allosteric modulator Ascorbic acid Flavonoid GABA receptor Quercetin 4 aminobutyric acid 4 aminobutyric acid A receptor 4 aminobutyric acid A receptor blocking agent 4 aminobutyric acid receptor ascorbic acid flavonoid histidine quercetin 4 aminobutyric acid A receptor 4 aminobutyric acid A receptor blocking agent ascorbic acid quercetin γ-aminobutyric acid Allosteric modulator allosterism animal article chemistry dose response drug antagonism drug effect human metabolism N-ethylmaleimide NEM antagonists and inhibitors drug effects γ-aminobutyric acid Allosteric modulator Ascorbic acid Flavonoid GABA GABA receptor N-ethylmaleimide NEM Quercetin Allosteric Regulation Animals Ascorbic Acid Dose-Response Relationship, Drug GABA-A Receptor Antagonists Histidine Humans Quercetin Receptors, GABA-A Allosteric Regulation Animals Ascorbic Acid Dose-Response Relationship, Drug GABA-A Receptor Antagonists Histidine Humans Quercetin Receptors, GABA-A |
| description |
Quercetin is a natural flavonoid widely distributed in plants that acts as a neuroprotective agent and modulates the activity of different synaptic receptors and ion channels, including the ionotropic GABA receptors. GABA Aρ1 receptors were shown to be antagonized by quercetin, but the mechanisms underlying these antagonistic actions are still unknown. We have analyzed here if the antagonistic action produced by quercetin on GABA Aρ1 receptors was related to its redox activity or due to alternative mechanism/s. Homomeric GABAAρ1 receptors were expressed in frog oocytes and GABA-evoked responses electro-physiologically recorded. Quercetin effects on GABAAρ1 receptors were examined in the absence or presence of ascorbic acid. Chemical protection of cysteines by selective sulfhydryl reagents and site directed mutagenesis experiments were also used to determine ρ1 subunit residues involved in quercetin actions. Quercetin antagonized GABAAρ1 receptor responses in a dose-dependent, fast and reversible manner. Quercetin inhibition was prevented in the presence of ascorbic acid, but not by thiol reagents that modify the extracellular Cys-loop of these receptors. H141, an aminoacidic residue located near to the ρ1 subunit GABA binding site, was involved in the allosteric modulation of GABAAρ1 receptors by several agents including ascorbic acid. Quercetin similarly antagonized GABA-evoked responses mediated by mutant H141DGABAAρ1 and wild-type receptors, but prevention exerted by ascorbic acid on quercetin effects was impaired in mutant receptors. Taken together the present results suggest that quercetin antagonistic actions on GABAAρ1 receptors are mediated through a redox-independent allosteric mechanism. © 2013 Elsevier B.V. All rights reserved. |
| author |
Calero, Cecilia Inés Calvo, Daniel Juan |
| author_facet |
Calero, Cecilia Inés Calvo, Daniel Juan |
| author_sort |
Calero, Cecilia Inés |
| title |
Quercetin antagonism of GABAAρ1 receptors is prevented by ascorbic acid through a redox-independent mechanism |
| title_short |
Quercetin antagonism of GABAAρ1 receptors is prevented by ascorbic acid through a redox-independent mechanism |
| title_full |
Quercetin antagonism of GABAAρ1 receptors is prevented by ascorbic acid through a redox-independent mechanism |
| title_fullStr |
Quercetin antagonism of GABAAρ1 receptors is prevented by ascorbic acid through a redox-independent mechanism |
| title_full_unstemmed |
Quercetin antagonism of GABAAρ1 receptors is prevented by ascorbic acid through a redox-independent mechanism |
| title_sort |
quercetin antagonism of gabaaρ1 receptors is prevented by ascorbic acid through a redox-independent mechanism |
| publishDate |
2013 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00142999_v714_n1-3_p274_Calero http://hdl.handle.net/20.500.12110/paper_00142999_v714_n1-3_p274_Calero |
| work_keys_str_mv |
AT caleroceciliaines quercetinantagonismofgabaar1receptorsispreventedbyascorbicacidthrougharedoxindependentmechanism AT calvodanieljuan quercetinantagonismofgabaar1receptorsispreventedbyascorbicacidthrougharedoxindependentmechanism |
| _version_ |
1768546003868188672 |