GABAA receptors mediating phasic and tonic inhibitory neurotrasmission in the retina and the hippocampus are targets of redox signalling

ANDREA BELTRÁN GONZÁLEZ; CECILIA I. CALERO; JAVIER GASULLA; F VICENTINI; J MARENSI; A OLAVIAGA; DANIEL J. CALVO

Mar del Plata

Congreso; XXX Annual meeting and SAN-ISNA small conference and course; 2015

Sociedad Argentina de Investigación en Neurociencias

Redox regulation is a key factor in the modulation of cellular pathways, including synapticneurotransmission. In contrast to irreversible oxidative damage, redox signalling ismediated by modifications of target proteins at particular redox-sensitive thiols thatoperate as redox-switches producing reversible changes on protein function(neurotransmitter receptors, voltage-gated ion channels and transporters). As redox statussignificantly fluctuates during normal and pathological conditions, the study of endogenousand pharmacological redox dependent synaptic modulation is fundamental forunderstanding the mechanisms controlling neuronal activity.We demonstrated that GABAA receptor function can be directly modulated by endogenousredox agents, through reversible thiol modification of cysteine residues located toextracellular or cytoplasmic domains. Either phasic GABAA receptors (mediating the fastcomponent of GABAergic neurotransmission elicited by GABA release) as tonic GABAAreceptors (which mediate the slow component elicited by ambient GABA), both in retinalbipolar cells and hippocampal CA1 pyramidal neurons, are sensitive to modulation exertedby redox agents. We identified a GABAA receptor variant carrying an intracellular sensorfor reactive oxygen species (H2O2) capable to induce allosteric transitions that modulatechannel activity. We also found that changes in ascorbic acid and nitric oxide levels can bedetected at the cys-loop to produce similar effects.