Adenosine receptor antagonists alter the stability of human epileptic GABAA receptors

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 39; pp. 15118 - 15123
• Main Authors: Roseti, Cristina, Martinello, Katiuscia, Fucile, Sergio, Piccari, Vanessa, Mascia, Addolorata, Di Gennaro, Giancarlo, Quarato, Pier Paolo, Manfredi, Mario, Esposito, Vincenzo, Cantore, Gianpaolo, Arcella, Antonella, Simonato, Michele, Fredholm, Bertil B, Limatola, Cristina, Miledi, Ricardo, Eusebi, Fabrizio
• Format: Journal Article
• Language: English
• Published: United States National Acad Sciences 30.09.2008; National Academy of Sciences
• Subjects: adenosine; Adenosine - metabolism; Adenosine - pharmacology; adenosine deaminase; Adenosine Deaminase - pharmacology; Adult; agonists; Animals; antagonists; anticonvulsants; Anticonvulsants - metabolism; Anticonvulsants - pharmacology; Biological Sciences; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; cortex; Epilepsy - metabolism; Female; GABA-A Receptor Agonists; gamma-aminobutyric acid; gamma-Aminobutyric Acid - metabolism; gamma-Aminobutyric Acid - pharmacology; Humans; Male; mice; neocortex; neurons; Neurons - metabolism; Oocytes; Purinergic P1 Receptor Antagonists; purinergic receptors; Pyramidal Tracts - metabolism; Pyrimidines - pharmacology; Quinazolines - pharmacology; Rats; Receptors, GABA-A - metabolism; Triazoles - pharmacology; Xanthines - pharmacology; Xenopus
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.0807277105

We examined how the endogenous anticonvulsant adenosine might influence γ-aminobutyric acid type A (GABA A ) receptor stability and which adenosine receptors (ARs) were involved. Upon repetitive activation (GABA 500 μM), GABA A receptors, microtransplanted into Xenopus oocytes from neurosurgically resected epileptic human nervous tissues, exhibited an obvious GABA A -current ( I GABA ) run-down, which was consistently and significantly reduced by treatment with the nonselective adenosine receptor antagonist CGS15943 (100 nM) or with adenosine deaminase (ADA) (1 units/ml), that inactivates adenosine. It was also found that selective antagonists of A2B (MRS1706, 10 nM) or A3 (MRS1334, 30 nM) receptors reduced I GABA run-down, whereas treatment with the specific A1 receptor antagonist DPCPX (10 nM) was ineffective. The selective A2A receptor antagonist SCH58261 (10 nM) reduced or potentiated I GABA run-down in ≈40% and ≈20% of tested oocytes, respectively. The ADA-resistant, AR agonist 2-chloroadenosine (2-CA) (10 μM) potentiated I GABA run-down but only in ≈20% of tested oocytes. CGS15943 administration again decreased I GABA run-down in patch-clamped neurons from either human or rat neocortex slices. I GABA run-down in pyramidal neurons was equivalent in A1 receptor-deficient and wt neurons but much larger in neurons from A2A receptor-deficient mice, indicating that, in mouse cortex, GABA A -receptor stability is tonically influenced by A2A but not by A1 receptors. I GABA run-down from wt mice was not affected by 2-CA, suggesting maximal ARs activity by endogenous adenosine. Our findings strongly suggest that cortical A2–A3 receptors alter the stability of GABA A receptors, which could offer therapeutic opportunities. A2A receptor A3 receptor microtransplantation into Xenopus oocyte temporal lobe epilepsy