Allosteric inhibition of the GABAAρ1 receptor function by L-cysteine.

VICENTINI, F; MARENSSI, J; BELTRÁN GONZALEZ A; CALVO, DJ

Mar del Plata

Congreso; XXX Congreso de la SAN; 2015

SAN

L-cysteine (L-cys) is a rate-limiting precursor for the glutathione synthesis in neurons that act either as neuroprotector or neuromodulator. Additionally, L-cys produces excitotoxic effects, which have been implicated in the pathogenesis of neurological disorders such as Parkinson´s and Alzheimer´s disease. However, the role of L-cys in the SNC still is far from being entirely understood.It has been also reported that L-cys can modulate the activity of ionic channels, for example is a redox modulator of calcium channels in rat peripheral nociceptors and a low potency agonist of the NMDA receptor in cultured rat hippocampal neurons. We have previously reported that L-cys inhibited the function of homomeric GABAAρ1 receptors. Now we extend this characterization by studying the underlying mechanism of action. Homomeric GABAAρ1 receptors were expressed in Xenopus laevis oocytes and GABA-evoked Cl- currents recorded by two-electrode voltage-clamp in the presence or absence of L-cys. Inhibition by L-cys was dose-dependent, reversible and voltage independent. DR curves for GABA were shifted to the right in the presence of L-cys and no effects were observed at saturating GABA concentrations. L-cys inhibition was insensitive to the irreversible cysteine alkilating agent NEM. The present results suggest that redox modulation is not involved during L-cys actions and that this intermediate metabolite more likely acts as a competitive antagonist of the GABAAρ1 receptors.