engleski

The effects of persistent activation of GABA-A receptors by neurotransmitter GABA

Gamma-aminobutyric acid (GABA) has an important role in the transmission of neural information throughout all brain regions, and is involved directly and/or indirectly in the control of many vital functions. In particular, various brain functions depend on the balance between excitatory and inhibitory neurotransmission. Given that GABA is the main inhibitory neurotransmitter, changes in its level might lead to numerous neurological and psychiatric disorders. GABA achieves its physiological actions mostly through GABA-A receptors. Persistent activation of GABAA receptors by GABA, as well as by agonists and drugs facilitating the action of GABA, triggers regulatory changes in receptor expression and/or function that are relevant to physiological, pathological and pharmacological conditions. Therefore, the aim of our study was to better understand the effects and mechanisms that underlie adaptive changes at GABA-A receptors following their prolonged exposure to neurotransmitter GABA itself. Prolonged exposure of human embryonic kidney (HEK 293) cells stably expressing recombinant α1β2γ2S GABAA receptors to GABA (1 mM) enhanced the maximum number of [3H]flunitrazepam, [3H]muscimol and [3H]TBOB binding sites without affecting their affinity. The GABA-induced enhancement in the maximum number of benzodiazepine binding sites was reduced by bicuculline (100 μM), GABA-A receptor antagonist, and by cycloheximide (10 μL/mL), a protein synthesis inhibitor. In parallel, prolonged GABA treatment has not produced allosteric uncoupling of GABA and benzodiazepine binding sites as evidenced by unaltered GABA-induced potentiation of [3H]flunitrazepam binding. In conclusion, prolonged exposure of recombinant GABAA receptors to GABA results in enhancement of total receptor number, probably due to increased synthesis rather than decreased degradation of receptor proteins. Moreover, persistent activation of receptors by GABA has not resulted in functional uncoupling of GABA and benzodiazepine binding sites. Additional studies are needed to determine the functional implications of such changes, as well as relevance of obtained results to the development of tolerance and dependence.

recombinant GABAA receptor ; GABA ; radioligand binding studies ; cell culture

nije evidentirano