A study was made of the modulation of -aminobutyric acid type A (GABAA) receptor stability by adenosine receptors (ARs), being adenosine an endogenous anticonvulsant in the brain. Upon repetitive activation (GABA 500 M) GABAA receptors, micro-transplanted 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 non-selective adenosine receptor antagonist CGS15943 (100 nM) or with adenosine deaminase (ADA, 1 U/ml), that converts adenosine into inosine. 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. Interestingly, 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-CLA, 10 M) 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, GABAA receptor stability is tonically influenced by A2A, not by A1 receptors. IGABA run-down from wt mice was not affected by 2-CLA, 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.
Adenosine receptor antagonists alter the stability of human epileptic GABAA receptors
SIMONATO, Michele;
2008
Abstract
A study was made of the modulation of -aminobutyric acid type A (GABAA) receptor stability by adenosine receptors (ARs), being adenosine an endogenous anticonvulsant in the brain. Upon repetitive activation (GABA 500 M) GABAA receptors, micro-transplanted 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 non-selective adenosine receptor antagonist CGS15943 (100 nM) or with adenosine deaminase (ADA, 1 U/ml), that converts adenosine into inosine. 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. Interestingly, 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-CLA, 10 M) 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, GABAA receptor stability is tonically influenced by A2A, not by A1 receptors. IGABA run-down from wt mice was not affected by 2-CLA, 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.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
