Adenosine receptor antagonists alter the stability of human epileptic GABAA receptors

Cristina Roseti, Katiuscia Martinello, Sergio Fucile, Vanessa Piccari, Addolorata Mascia, Giancarlo Di Gennaro, Pier Paolo Quarato, Mario Manfredi, Vincenzo Esposito, Gianpaolo Cantore, Antonella Arcella, Michele Simonato, Bertil B. Fredholm, Cristina Limatola, Ricardo Miledi, Fabrizio Eusebi

Research output: Contribution to journalArticle

Abstract

We examined how the endogenous anticonvulsant adenosine might influence γ-aminobutyric acid type A (GABAA) receptor stability and which adenosine receptors (ARs) were involved. Upon repetitive activation (GABA 500μM), GABAA receptors, microtransplanted into Xenopus oocytes from neurosurgically resected epileptic human nervous tissues, exhibited an obvious GABAA-current (IGABA) 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 IGABA 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 IGABA run-down in ≈40% and ≈20% of tested oocytes, respectively. The ADA-resistant, AR agonist 2-chloroadenosine (2-CA) (10 μM) potentiated IGABA run-down but only in ≈20% of tested oocytes. CGS15943 administration again decreased IGABA run-down in patch-clamped neurons from either human or rat neocortex slices. IGABA 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. IGABA 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 GABAA receptors, which could offer therapeutic opportunities.

Original languageEnglish
Pages (from-to)15118-15123
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number39
DOIs
Publication statusPublished - Sep 30 2008

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Keywords

  • A2A receptor
  • A3 receptor
  • Microtransplantation into Xenopus oocyte
  • Temporal lobe epilepsy

ASJC Scopus subject areas

  • General

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