Subunit composition critically define ROS modulation of GABAA receptors

LÓPEZ PAZOS, MANUEL I; DEL VAS M; BELTRÁN GONZÁLEZ AN; CALVO DJ

Buenos Aires

Congreso; XXXVII Reunión Anual de la Sociedad Argentina de Neurociencias; 2022

Sociedad Argentina de Neurociencias

Reactive oxygen species (ROS) were involved in neuronal signalling and plasticity in normal physiology, aging and neurodegenerative disorders. Besides, GABAergic neurotransmission is sensitive to redox agents, including ROS. We previously reported the modulation of tonic responses mediated by GABAAρ1 receptors by hydrogen peroxide (H2O2) through thiol modification of cysteines. We also showed that endogenous redox agents modulate phasic GABAA receptor subtypes, but diverse molecular mechanisms of action appear to underlie these effects.We characterized H2O2 effects on different GABAA receptor subtypes by expression in Xenopus laevis oocytes followed by electrophysiological recording. In the presence of H2O2 (1mM) responses mediated by receptors containing αβ and αβδ subunits were potentiated, while the presence of the γ2 subunit conferred resistance to ROS modulation. H2O2 effects on GABAAα1β2 responses were reversible, dose and use-dependent, voltage-insensitive and partially prevented by irreversible alkylation of sulfhydryl groups with NEM. Increases in agonist concentration partially reduced effects exerted by H2O2. Concentration-response curves in the presence of H2O2 showed a leftward shift, compared to control values, and an increase in the maximal response. Further experiments will help to describe the actual mechanisms of action underlying the effects of H2O2 on the different GABAA receptor subtypes.