Blockage of A _2A and A ₃ adenosine receptors decreases the desensitization of human GABA _A receptors microtransplanted to Xenopus oocytes

Abstract

We previously found that the endogenous anticonvulsant adenosine, acting through A 2A and A3 adenosine receptors (ARs), alters the stability of currents (I GABA) generated by GABAA receptors expressed in the epileptic human mesial temporal lobe (MTLE). Here we examined whether ARs alter the stability (desensitization) of I GABA expressed in focal cortical dysplasia (FCD) and in periglioma epileptic tissues. The experiments were performed with tissues from 23 patients, using voltage-clamp recordings in Xenopus oocytes microinjected with membranes isolated from human MTLE and FCD tissues or using patch-clamp recordings of pyramidal neurons in epileptic tissue slices. On repetitive activation, the epileptic GABA A receptors revealed instability, manifested by a large I GABA rundown, which in most of the oocytes (Ϸ70%) was obviously impaired by the new A 2A antagonists ANR82, ANR94, and ANR152. In most MTLE tissue-microtransplanted oocytes, a new A 3 receptor antagonist (ANR235) significantly improved IGABA stability. Moreover, patch-clamped pyramidal neurons from human neocortical slices of periglioma epileptic tissues exhibited altered I GABA rundown on ANR94 treatment. Our findings indicate that antagonizing A 2A and A3 receptors increases the IGABA stability in different epileptic tissues and suggest that adenosine derivatives may offer therapeutic opportunities in various forms of human epilepsy.epilepsy ͉ focal cortical dysplasia

The A3Adenosine Receptor: History and Perspectives

“…Accordingly, it has also been reported that A 3 ARs decrease the stability of currents generated by gamma aminobutyric acid in different epileptic tissues, thus suggesting that adenosine antagonists may offer therapeutic opportunities in various forms of human epilepsy (Roseti et al, 2009).…”

Adenosine Release during Seizures Attenuates GABAAReceptor-Mediated Depolarization

“…GABA A R reversal potential and conductance are not altered by AR activation Other mechanisms that could contribute to the adenosine-induced effect upon postsynaptic GABA A R-mediated responses include alterations in Cl Ϫ homeostasis mechanisms (Kaila et al, 1997;Dzhala et al, 2005Dzhala et al, , 2010Jin et al, 2005;Huberfeld et al, 2007) and/or changes in the conductance of the GABA A R (Roseti et al, 2008(Roseti et al, , 2009). To investigate whether AR activation affects Cl Ϫ homeostasis we measured E GABAA under control conditions and following bath application of adenosine.…”

Enhancement of GABA A -current run-down in the hippocampus occurs at the first spontaneous seizure in a model of temporal lobe epilepsy

“…In particular, the repetitive activation of GABA A receptors produces a use-dependent decrease (rundown) of the membrane currents evoked by GABA (I GABA ), a phenomenon markedly enhanced in hippocampal and cortical neurons of TLE patients (5,6). This phenomenon is significantly prevented by BDNF, adenosine derivatives, and phosphatase inhibitors (7)(8)(9)(10), suggesting that phosphorylation of GABA A receptors and/or associated proteins may be linked to the increase in run-down (11). Understanding the role of I GABA run-down in the disease and its mechanisms may allow development of medical alternatives to surgical resection.…”