title: Adenosine receptor antagonists alter the stability of human epileptic GABAA receptors.
abstract: We examined how the endogenous anticonvulsant adenosine might influence gamma-aminobutyric acid type A (GABA(A)) receptor stability and which adenosine receptors (ARs) were involved. Upon repetitive activation (GABA 500 microM), 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 approximately 40% and approximately 20% of tested oocytes, respectively. The ADA-resistant, AR agonist 2-chloroadenosine (2-CA) (10 microM) potentiated I(GABA) run-down but only in approximately 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.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti and Dipartimento di Fisiologia Umana e Farmacologia, Centro di Eccellenza di Biologia e Medicina Molecolare, Università di Roma La Sapienza, Piazzale A. Moro 5, I-00185 Rome, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Roseti
authors.forename: Katiuscia
authors.initials: K
authors.lastname: Martinello
authors.forename: Sergio
authors.initials: S
authors.lastname: Fucile
authors.forename: Vanessa
authors.initials: V
authors.lastname: Piccari
authors.forename: Addolorata
authors.initials: A
authors.lastname: Mascia
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Di Gennaro
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Quarato
authors.forename: Mario
authors.initials: M
authors.lastname: Manfredi
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Esposito
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Cantore
authors.forename: Antonella
authors.initials: A
authors.lastname: Arcella
authors.forename: Michele
authors.initials: M
authors.lastname: Simonato
authors.forename: Bertil B
authors.initials: BB
authors.lastname: Fredholm
authors.forename: Cristina
authors.initials: C
authors.lastname: Limatola
authors.forename: Ricardo
authors.initials: R
authors.lastname: Miledi
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Eusebi
mesh_terms: D000241:Adenosine / Q000378:metabolism* / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000494:pharmacology; D000328:Adult; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism* / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004827:Epilepsy / Q000378:metabolism*; D005260:Female; D058785:GABA-A Receptor Agonists; D006801:Humans; D008297:Male; D009474:Neurons / Q000378:metabolism; D009865:Oocytes; D058915:Purinergic P1 Receptor Antagonists; D011712:Pyramidal Tracts / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology; D014981:Xenopus; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology
chemical_list: C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D000927:Anticonvulsants; D058785:GABA-A Receptor Agonists; C484841:GABRA2 protein, human; C546257:GABRA3 protein, human; C546258:Gabra3 protein, mouse; C546259:Gabra3 protein, rat; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines; D011799:Quinazolines; D011963:Receptors, GABA-A; D014230:Triazoles; D014970:Xanthines; D005680:gamma-Aminobutyric Acid; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000243:Adenosine Deaminase; D000241:Adenosine; C052410:9-chloro-2-(2-furyl)-(1,2,4)triazolo(1,5-c)quinazolin-5-imine