@article{cde8a0c0b51f40b1bd1c3e749757b8b5,
title = "Dissecting the molecular determinants of GABAA receptors current rundown, a hallmark of refractory human epilepsy",
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 twoelectrode 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.",
keywords = "Electrophysiology, GABA receptor, GABA rundown, Human epilepsy",
author = "Pierangelo Cifelli and {di Angelantonio}, Silvia and Veronica Alfano and Alessandra Morano and {de Felice}, Eleonora and Eleonora Aronica and Gabriele Ruffolo and Eleonora Palma",
note = "Funding Information: This research was funded by grants from AICE-FIRE; ?Bando di Ateneo (Sapienza University)?, grant n? RM11916B84D24429 (to E.P.).; the CrestOptics-IIT JointLab for Advanced Microscopy (to S.D.A.), the Bio3DBrain FSE 2014-2020 Regione Lazio (to S.D.A.). This work was partially supported by Sapienza University and Fondazione Istituto Italiano di Tecnologia to S.D.A. This project has received funding from the European Union?s Horizon 2020 Research and Innovation Programme under grant agreement No. 952455.G.R. was supported by BE-FOR-ERC program (Sapienza University). Funding Information: Funding: This research was funded by grants from AICE-FIRE; “Bando di Ateneo (Sapienza University)”, grant n◦ RM11916B84D24429 (to E.P.).; the CrestOptics-IIT JointLab for Advanced Microscopy (to S.D.A.), the Bio3DBrain FSE 2014-2020 Regione Lazio (to S.D.A.). This work was partially supported by Sapienza University and Fondazione Istituto Italiano di Tecnologia to S.D.A. This project has received funding from the European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme under grant agreement No. 952455. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
doi = "https://doi.org/10.3390/brainsci11040441",
language = "English",
volume = "11",
journal = "Brain sciences",
issn = "2076-3425",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "4",
}