Activity-dependent regulation of GABA-A receptor function

M. L. GUTIÉRREZ; M. C. GRAVIELLE

Tandil, Provincia de Buenos Aires

Congreso; XL Reunión Anual de la Asociación Argentina de Farmacología Experimental; 2008

Asociación Argentina de Farmacología Experimental

Alterations in the GABAA receptor function are associated with tolerance to the sedative-hypnotic effects of benzodiazepines. Chronic activation of GABAA receptors by GABA has been shown to induce down-regulation of receptor number and uncoupling of GABA/benzodiazepine site interactions with a half-time of 24 h. In a previous work we reported that a single brief exposure of cultured neocortical neurons to GABA for 5-10 min (t1/2=3 min) initiates a process that results in uncoupling hours later (t1/2=1 h) in the absence of a change in receptor number, providing a paradigm to selectively study the mechanism of uncoupling. Uncoupling is contingent upon receptor activation and is accompanied by down-regulation of selective receptor subunits. In order to determine whether uncoupling is produced by positive allosteric modulators we studied here the effect of brief applications of benzodiazepines. Results from these experiments indicated that diazepam treatment induced a small but significant uncoupling that is blocked by flumazenil. To further analyze the mechanism of uncoupling we first investigated whether uncoupling is mediated by the activation of a protein kinase cascade. Our results showed that the protein kinase inhibitors studied blocked the GABA-induced uncoupling suggesting a role of phosphorylation on the mechanism of uncoupling. This activity-dependent modulation of GABAA receptor function may be relevant to physiological and pharmacological conditions where synaptic receptors are exposed to GABA agonists for several minutes.