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

BELTRÁN GONZALEZ A; CALERO CI; GASULLA J; VICENTINI, F; MARENSSI, J; OLAVIAGA, A; CALVO, DJ

Mar del Plata

Congreso; XXX Congreso de la SAN; 2015

SAN

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