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Content Provider | World Health Organization (WHO)-Global Index Medicus |
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Author | Beltrán González, Andrea N. Gasulla, Javier Calvo, Daniel J. |
Description | Author Affiliation: Beltrán González AN ( Ingebi Conicet UBA, Buenos Aires, Argentina.) |
Abstract | BACKGROUND AND PURPOSE: Reactive oxygen species (ROS) are normally involved in cell oxidative stress but also play a role as cellular messengers in redox signalling; for example, modulating the activity of neurotransmitter receptors and ion channels. However, the direct actions of ROS on GABAA receptors were not previously demonstrated. In the present work, we studied the effects of ROS on GABAA ρ1 receptor function. EXPERIMENTAL APPROACH: GABAA ρ1 receptors were expressed in oocytes and GABA-evoked responses electrophysiologically recorded in the presence or absence of ROS. Chemical protection of cysteines by selective sulfhydryl reagents and site-directed mutagenesis studies were used to identify protein residues involved in ROS actions. KEY RESULTS: GABAA ρ1 receptor-mediated responses were significantly enhanced in a concentration-dependent and reversible manner by H2O2. Potentiating effects were attenuated by a free radical scavenger, lipoic acid or an inhibitor of the Fenton reaction, deferoxamine. Each ρ1 subunit contains only three cysteine residues, two extracellular at the Cys-loop (C¹77 and C¹9¹) and one intracellular (C³64) at the M3-M4 linker. Mutant GABAA ρ1 receptors in which C³64 was exchanged by alanine were completely insensitive to modulation, implying that this site, rather than a cysteine in the Cys-loop, is essential for ROS modulation. CONCLUSION AND IMPLICATIONS: Our results show that the function of GABAA ρ1 receptors is enhanced by ROS and that the intracellular C³64 is the sensor for ROS actions. |
ISSN | 00071188 |
e-ISSN | 14765381 |
Journal | British Journal of Pharmacology |
Issue Number | 9 |
Volume Number | 171 |
Language | English |
Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
Publisher Date | 2014-05-01 |
Publisher Place | Great Britain (UK) |
Access Restriction | Open |
Subject Keyword | Intracellular Fluid Metabolism Reactive Oxygen Species Receptors, GABA-A Animals Cysteine Chemistry Dose-Response Relationship, Drug Hydrogen Peroxide Pharmacology Oocytes Oxidation-Reduction Xenopus Laevis |
Content Type | Text |
Resource Type | Article |
Subject | Pharmacology |
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