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Neuroscience ; 281: 208-15, 2014 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-25286387

RESUMO

Caffeine, a methylated derivative of xanthine and widely consumed psychoactive substance, acts in several targets in the nervous system. We investigated its role in retinal explants of chick embryo analyzing the role of purinergic receptors in [(3)H]-GABA release induced by d-aspartate (d-asp). d-Asp increases GABA-release 4.5-fold when compared to basal levels from 13-day-old chick embryo retinal explants. Caffeine 500µM elevated d-asp-induced GABA release in 60%. The release was inhibited in the presence of NNC-711, a GABA transporter-1 (GAT-1) blocker or by MK-801, an N-methyl-d-aspartate receptor (NMDAR) antagonist. Caffeine did not modify [(3)H]-GABA uptake carried out for 5, 10, 30 and 60min and did not increase the release of d-asp or glutamate at basal or stimulated conditions. The caffeine effect was mimicked by the adenosine A1 receptor antagonist DPCPX and by the adenylyl cyclase (AC) activator forskolin. It was also blocked by the protein kinase A (PKA) inhibitor H-89, tyrosine kinase inhibitor genistein or by the src family kinase (SFK) inhibitor PP1. Forskolin-stimulated cyclic adenosine monophosphate (cAMP) levels were reduced in the presence of the A1 receptor agonist CHA. Western blot analysis revealed that 500µM caffeine increased phosphoGluN2B expression levels in approximately 60% when compared to total GluN2B levels in embryonic E13 retina. The GluN2B subunit-containing NMDAR antagonist ifenprodil inhibited the caffeine effect. Our results suggest that caffeine potentiates d-asp-induced GABA release, which is mediated by GAT-1, via inhibition of adenosine A1 receptor and activation of the PKA pathway. Regulation of NMDAR by phosphorylation of GluN2B subunit by a SFK may also be involved in the effect promoted by caffeine.


Assuntos
Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Ácido D-Aspártico/farmacologia , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Receptor A1 de Adenosina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Retina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Animais , Embrião de Galinha , Proteínas Quinases Dependentes de AMP Cíclico/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de GABA/efeitos dos fármacos , Receptor A1 de Adenosina/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Retina/efeitos dos fármacos , Ácido gama-Aminobutírico/efeitos dos fármacos
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