On the role of the gamma2 subunit in the modulation of GABAA receptors by endogenous redox agents

LÓPEZ PAZOS MI; DEL VAS M; BELTRÁN GONZÁLEZ AN; CALVO DJ

Córdoba

Congreso; XXXIII Congreso anual de la Sociedad Argentina de Investigaciones en Neurociencias; 2018

Sociedad Argentina de Investigaciones en Neurociencias

Endogenous reactive oxygen species and antioxidants participate in neuronal signalling and plasticity in normal physiology, during aging and in the development of neurodegenerative disorders. GABAergic neurotransmission was shown to be sensitive to redox agents. We demonstrated that tonic responses mediated by GABAAρ1 receptors can be modulated by H2O2, ascorbic acid (Asc), glutathione and nitric oxide through thiol modification of cysteines. We also identified endogenous redox agents that modulate GABAA receptors involved in fast inhibitory neurotransmission in the retina and hippocampus, but the molecular mechanisms implied remain elusive. Now we analyzed the effects of H2O2 and Asc on GABAAα1β2 and GABAAα1β2γ2L receptors expressed in Xenopus laevis oocytes using two-electrode voltage-clamp recording of GABA-evoked Cl- currents. H2O2 and Asc modulated GABAAα1β2 responses. H2O2 exerted a dose-dependent, reversible and voltage-insensitive potentiating effect which was not prevented by irreversible alkylation of sulphydryl groups with NEM, whereas Asc induced a dual modulation with an early inhibition and a subsequent phase of potentiation. In contrast, GABAAα1β2γ2L receptors activity was not altered during superfusion of H2O2 and Asc, suggesting that the γ2 subunit conferred a relative insensitivity to these two endogenous agents. Additional experiments to elucidate the mechanisms of action underlying the effects of H2O2 and Asc on GABAAα1β2 receptors are being performed.