Dynamic Regulation of the GABA_A Receptor Function by Redox Mechanisms

Abstract

Oxidizing and reducing agents, which are currently involved in cell metabolism and signaling pathways, can regulate fast inhibitory neurotransmission mediated by GABA receptors in the nervous system. A number of in vitro studies have shown that diverse redox compounds, including redox metabolites and reactive oxygen and nitrogen species, modulate phasic and tonic responses mediated by neuronal GABA A receptors through both presynaptic and postsynaptic mechanisms. We review experimental data showing that many redox agents, which are normally present in neurons and glia or are endogenously generated in these cells under physiologic states or during oxidative stress (e.g., hydrogen peroxide, superoxide and hydroxyl radicals, nitric oxide, ascorbic acid, and glutathione), induce potentiating or inhibiting actions on different native and recombinant GABA A receptor subtypes. Based on these results, it is thought that redox signaling might represent a homeostatic mechanism that regulates the function of synaptic and extrasynaptic GABA A receptors in physiologic and pathologic conditions.

Redox Post-translational Modifications of Protein Thiols in Brain Aging and Neurodegenerative Conditions—Focus on S-Nitrosation

“…The potential synergistic effect on drug efficacy of the combination of an existing drug and a nitro group has also been tested with the FDA-approved compound Clomethiazole (CMZ). CMZ is a well-established neuroprotective potentiator of the redox-sensitive gamma-aminobutyric acid receptor (GABAR; Castel and Vaudry, 2001 ; Wilby and Hutchinson, 2004 ; Gasulla et al, 2012 ; Dejanovic and Schwarz, 2014 ; Vandevrede et al, 2014 ; Calvo and Beltrán González, 2016 ). Crucially, NMZ/GT-1061, a CMZ compound analog possessing a nitro group, was shown in AD mouse models to significantly reduce Aβ deposition and cognitive decline, and to restore neuronal plasticity (Qin et al, 2012 ; Luo et al, 2015 , 2016 ; Hollas et al, 2019 ); however, it remains unknown whether NO-mediated redox PTMs on GABAR play a part in the improved beneficial therapeutic effects provided by NMZ treatment.…”

Sleep‐inducing effect of Passiflora incarnata L. extract by single and repeated oral administration in rodent animals

“…Since high concentrations of PI were also used in the in vivo experiment, the in vitro experiment was conducted at the most valid high concentration (6 μg/ml). The increase or decrease in the expression of ROS expression is not only related to cell damage or expression of cytokines in cells, but also acts an important factor required for the activity of GABA (Calvo & Beltran Gonzalez, 2016). The increase or decrease in the expression of ROS expression is not only related to cell damage or expression of cytokines in cells, but also acts an important factor required for the activity of GABA (Calvo & Beltran Gonzalez, 2016).…”

Supraphysiological Levels of Oxygen Exposure During the Neonatal Period Impairs Signaling Pathways Required for Learning and Memory

“…In rodent models, over-activation of GABA A and GABA B receptors is known to cause learning and memory deficits, especially spatial navigation deficits, and the inhibition of GABA A 50 and GABA B 51 improves deficits in demyelination and vascular models of dementia. Studies have shown that reactive oxygen species increase the potency of GABA A , increase GABA A receptor-mediated tonic current in hippocampal neurons in rodent oxidative stress models 52 , and modulates GABA A function 53 . Our study showed that oxidative stress increases the expression of GABA A receptors, specifically α3, α5, and ɤ2 subunits in the hippocampus.…”