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XB-ART-57993
Brain Sci 2021 Mar 30;114:. doi: 10.3390/brainsci11040441.
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Dissecting the Molecular Determinants of GABAA Receptors Current Rundown, a Hallmark of Refractory Human Epilepsy.

Cifelli P , Di Angelantonio S , Alfano V , Morano A , De Felice E , Aronica E , Ruffolo G , Palma E .


Abstract
GABAA receptors-(Rs) are fundamental for the maintenance of an efficient inhibitory function in the central nervous system (CNS). Their dysfunction is associated with a wide range of CNS disorders, many of which characterized by seizures and epilepsy. Recently, an increased use-dependent desensitization due to a repetitive GABA stimulation (GABAA current rundown) of GABAARs has been associated with drug-resistant temporal lobe epilepsy (TLE). Here, we aimed to investigate the molecular determinants of GABAA current rundown with two different heterologous expression systems (Xenopus oocytes and human embryonic kidney cells; HEK) which allowed us to manipulate receptor stoichiometry and to study the GABAA current rundown on different GABAAR configurations. To this purpose, we performed electrophysiology experiments using two-electrode voltage clamp in oocytes and confirming part of our results in HEK. We found that different degrees of GABAA current rundown can be associated with the expression of different GABAAR β-subunits reaching the maximum current decrease when functional α1β2 receptors are expressed. Furthermore, the blockade of phosphatases can prevent the current rundown observed in α1β2 GABAARs. Since GABAAR represents one important therapeutic target in the treatment of human epilepsy, our results could open new perspectives on the therapeutic management of drug-resistant patients showing a GABAergic impairment.

PubMed ID: 33808090
PMC ID: PMC8066365
Article link: Brain Sci
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: gabarap
GO keywords: phosphorylation [+]

Disease Ontology terms: Rett syndrome [+]

Article Images: [+] show captions
References [+] :
Berg, Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. 2010, Pubmed