Flumazenil-insensitive modulation of GABA-Aρ receptors by benzodiazepines.

BELTRÁN GONZALEZ A; PE POMATA; GASULLA J; CALVO DJ

La Falda, Cordoba

Congreso; XXVIII Congreso anual de la Sociedad Argentina de Investigaciones en Neurociencias.; 2013

GABA-A receptors are ligand-gated ion-channels that mediate most of the inhibitory neurotransmission in the CNS. They can be allosterically modulated by benzodiazepines (BZ) to produce anxiolytic and sedative effects in vivo. GABA-A receptors with diverse subunit composition and arrangement arise from particular combinations of five subunits, each belonging to different classes (, which impart distinctive pharmacological and electrophysiological properties to the receptor subtypes.  subunits are critical for the typical pharmacological potentiating effects of BZs on GABA-A receptors to happen, while the retinal homomeric GABA-A receptors still are considered insensitive to these drugs. However, preliminary experiments from our lab suggested that this may not be the case. We expressed GABA-A1 receptors in Xenopus laevis oocytes and recorded, using two-electrode voltage-clamp, the GABA-evoked chloride currents in the presence or absence of diverse BZ. Diazepam, a common minor tranquilizer, significantly potentiated GABA-A1 receptor mediated responses. Meanwhile, the atypical anxiogenic BZ 4´-chlorodiazepam exhibited a biphasic effect depending on the GABA concentration (potentiation below 1M GABA and inhibition above that concentration). All BZ actions were dose dependent and occurred in the M range; BZ effects were also easily reversible and voltage independent. Co-application of the selective antagonist flumazenil had no effect on BZ modulation.