Flumazenil decreases surface expression of α4β2δ GABAA receptors by increasing the rate of receptor internalization.

Flumazenil decreases surface expression of α4β2δ GABAA receptors by increasing the rate of receptor internalization.
Brain Res Bull. 2015 Nov 21;
Authors: Kuver A, Smith SS
Abstract
Increases in expression of α4βδ GABAA receptors (GABARs), triggered by fluctuations in the neurosteroid THP (3α-OH-5α[β]-pregnan-20-one), are associated with changes in mood and cognition. We tested whether α4βδ trafficking and surface expression would be altered by in vitro exposure to flumazenil, a benzodiazepine ligand which reduces α4βδ expression in vivo. We first determined that flumazenil (100nM-100μM, IC50=∼1μM) acted as a negative modulator, reducing GABA (10μM)-gated current in the presence of 100nM THP (to increase receptor efficacy), assessed with whole cell patch clamp recordings of recombinant α4β2δ expressed in HEK-293 cells. Surface expression of recombinant α4β2δ receptors was detected using a 3XFLAG reporter at the C-terminus of α4 (α4F) using confocal immunocytochemical techniques following 48h exposure of cells to GABA (10μM)+THP (100nM). Flumazenil (10μM) decreased surface expression of α4F by ∼60%, while increasing its intracellular accumulation, after 48h. Reduced surface expression of α4β2δ after flumazenil treatment was confirmed by decreases in the current responses to 100nM of the GABA agonist gaboxadol. Flumazenil-induced decreases in surface expression of α4β2δ were prevented by the dynam...

Source: Brain Research Bulletin - November 21, 2015 Category: Neurology Authors: Kuver A, Smith SS Tags: Brain Res Bull Source Type: research