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Abstract:

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.

Registro:

Documento: Artículo
Título:Quercetin antagonism of GABAAρ1 receptors is prevented by ascorbic acid through a redox-independent mechanism
Autor:Calero, C.I.; González, A.N.B.; Gasulla, J.; Alvarez, S.; Evelson, P.; Calvo, D.J.
Filiación:Laboratorio de Neurobiología Celular y Molecular, Instituto de Investigaciones en Ingenieria Genetica y Biologia Molecular (INGEBI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Vuelta de Obligado 2490, C1428ADN Ciudad Autónoma de Buenos Aires, Argentina
Laboratorio de Biología de Radicales Libres, IBIMOL, CONICET, FFyB UBA, Junín 954, C1113AAB Ciudad Autónoma de Buenos Aires, Argentina
Laboratorio de Neurociencia Integrativa, Depto. de Física, FCEN UBA CONICET, Intendente Güiraldes 2160, Pabellón I, C1428EGA Ciudad Autónoma de Buenos Aires, Argentina
Palabras clave: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
Año:2013
Volumen:714
Número:1-3
Página de inicio:274
Página de fin:280
DOI: http://dx.doi.org/10.1016/j.ejphar.2013.07.044
Título revista:European Journal of Pharmacology
Título revista abreviado:Eur. J. Pharmacol.
ISSN:00142999
CODEN:EJPHA
CAS:4 aminobutyric acid, 28805-76-7, 56-12-2; ascorbic acid, 134-03-2, 15421-15-5, 50-81-7; histidine, 645-35-2, 7006-35-1, 71-00-1; quercetin, 117-39-5; Ascorbic Acid, PQ6CK8PD0R; GABA-A Receptor Antagonists; Histidine, 4QD397987E; Quercetin, 9IKM0I5T1E; Receptors, GABA-A; Ascorbic Acid; GABA-A Receptor Antagonists; Histidine; Quercetin; Receptors, GABA-A
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00142999_v714_n1-3_p274_Calero

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Citas:

---------- APA ----------
Calero, C.I., González, A.N.B., Gasulla, J., Alvarez, S., Evelson, P. & Calvo, D.J. (2013) . Quercetin antagonism of GABAAρ1 receptors is prevented by ascorbic acid through a redox-independent mechanism. European Journal of Pharmacology, 714(1-3), 274-280.
http://dx.doi.org/10.1016/j.ejphar.2013.07.044
---------- CHICAGO ----------
Calero, C.I., González, A.N.B., Gasulla, J., Alvarez, S., Evelson, P., Calvo, D.J. "Quercetin antagonism of GABAAρ1 receptors is prevented by ascorbic acid through a redox-independent mechanism" . European Journal of Pharmacology 714, no. 1-3 (2013) : 274-280.
http://dx.doi.org/10.1016/j.ejphar.2013.07.044
---------- MLA ----------
Calero, C.I., González, A.N.B., Gasulla, J., Alvarez, S., Evelson, P., Calvo, D.J. "Quercetin antagonism of GABAAρ1 receptors is prevented by ascorbic acid through a redox-independent mechanism" . European Journal of Pharmacology, vol. 714, no. 1-3, 2013, pp. 274-280.
http://dx.doi.org/10.1016/j.ejphar.2013.07.044
---------- VANCOUVER ----------
Calero, C.I., González, A.N.B., Gasulla, J., Alvarez, S., Evelson, P., Calvo, D.J. Quercetin antagonism of GABAAρ1 receptors is prevented by ascorbic acid through a redox-independent mechanism. Eur. J. Pharmacol. 2013;714(1-3):274-280.
http://dx.doi.org/10.1016/j.ejphar.2013.07.044