Glutathione effects on GABAA receptors

BELTRÁN GONZÁLEZ AN; LÓPEZ PAZOS MI; PARLATO MI; DI MARTINO T; DEL VAS M; CALVO DJ

San Luis

Congreso; XLVIII Reunión Anual de la Sociedad Argentina de Biofísica; 2019

Sociedad Argentina de Biofísica

Glutathione (GSH) is the major antioxidant and redox buffer in the brain. GSH exerts a protective role against oxidative stress, in the detoxification of H2O2 and lipid peroxides, scavenging of OH? and regeneration of the most important antioxidants (Vit C and E). GSH is also involved in the regulation of many synaptic functions and in neuronal plasticity. Furthermore, GSH deficiency has been implicated in neurodegenerative diseases. Previous reports demonstrated that GSH modulates GABAergic neurotransmission, although experimental evidence is limited. We have previously described that spontaneous responses exhibited by homomeric GABAAβ3 receptor increased in the presence of GSH and that effects were insensitive to irreversible alkylation of sulphydryl groups within the β3 subunits by N-ethylmaleimide, discarding a redox-dependent mechanism mediated by cysteine. In this study we evaluated the effect of GSH in different phasic and tonic GABAA receptor subtypes. Human GABAA receptors were expressed in Xenopus laevis oocytes and GABA-evoked Cl- currents were recorded by two-electrode voltage-clamp. GSH (1mM) potentiated GABAAα4β3, GABAAα5β3 and GABAAα1β2 receptor responses elicited by GABA (~EC10). In contrast, GSH had no effect on GABAAα4β3δ, GABAα4β3γ2 and GABAAα1β2γ2 receptors. Previous results showed that GSH prevented inhibition of GABAAβ3 responses by Zn2+, the second most abundant trace metal in neurons. Considering the different sensitivity that GABAAαβ and GABAαβγ/δ receptors exhibit to Zn2+, we performed experiments in the presence of Tricine, a Zn2+ chelator. Tricine (10mM) prevented GSH potentiation of GABAAα1β2 responses, suggesting that GSH may exert its action indirectly, via chelation of Zn2+ traces contained in the buffer medium. Given the importance of Zn2+ as an allosteric modulator of GABAA receptors and the role of GSH as a neuronal antioxidant, this might represent a relevant mechanism of control of the GABAergic neurotransmission.