Reactive Oxygen Species in the Regulation of the GABA Mediated Inhibitory Neurotransmission

Abstract

Reactive oxygen species (ROS) are best known for being involved in cellular metabolism and oxidative stress, but also play important roles in cell communication. ROS signaling has become increasingly recognized as a mechanism implicated in the regulation of synaptic neurotransmission, under both physiological and pathological conditions. Hydrogen peroxide (H₂O₂) and superoxide anion are the main biologically relevant endogenous ROS in the nervous system. They are predominantly produced in the mitochondria of neurons and glial cells and their levels are tightly regulated by the antioxidant cell machinery, which allows for dynamic signaling through these agents. Physicochemical and biological properties of H₂O₂ enable it to effectively play an important role in signaling. This review brings up some or the most significant evidence supporting ROS as signaling agents in the nervous system and summarizes data showing that ROS modulate γ-aminobutyric acid (GABA)-mediated neurotransmission by pre- and postsynaptic mechanisms. ROS induce changes on both, the activity of phasic and tonic GABA_A receptors and GABA release from presynaptic terminals. Based on these facts, ROS signaling is discussed as a possible selective mechanism linking cellular metabolism to inhibitory neurotransmission through the direct or indirect modulation of the GABA_A receptor function. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.

Keywords: GABA(A) receptor; hydrogen peroxide; inhibitory neurotransmission; reactive oxygen species; redox signaling.