Blockage of A₂A and A₃ adenosine receptors decreases the desensitization of human GABAA receptors microtransplanted to Xenopus oocytes

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-09, Vol.106 (37), p.15927-15931
• Main Authors: Roseti, Cristina, Palma, Eleonora, Martinello, Katiuscia, Fucile, Sergio, Morace, Roberta, Esposito, Vincenzo, Cantore, Gianpaolo, Arcella, Antonietta, Giangaspero, Felice, Aronica, Eleonora, Mascia, Addolorata, Di Gennaro, Giancarlo, Quarato, Pier Paolo, Manfredi, Mario, Cristalli, Gloria, Lambertucci, Catia, Marucci, Gabriella, Volpini, Rosaria, Limatola, Cristina, Eusebi, Fabrizio
• Format: Article
• Language: English
• Subjects: Biological Sciences
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0907324106

We previously found that the endogenous anticonvulsant adenosine, acting through A₂A and A₃ adenosine receptors (ARs), alters the stability of currents (IGABA) generated by GABAA receptors expressed in the epileptic human mesial temporal lobe (MTLE). Here we examined whether ARs alter the stability (desensitization) of IGABA 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 GABAA receptors revealed instability, manifested by a large IGABA rundown, which in most of the oocytes ([almost equal to]70%) was obviously impaired by the new A₂A antagonists ANR82, ANR94, and ANR152. In most MTLE tissue-microtransplanted oocytes, a new A₃ receptor antagonist (ANR235) significantly improved IGABA stability. Moreover, patch-clamped pyramidal neurons from human neocortical slices of periglioma epileptic tissues exhibited altered IGABA rundown on ANR94 treatment. Our findings indicate that antagonizing A₂A 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.