Adenosine A2A receptors regulate the extracellular accumulation of excitatory amino acids upon metabolic dysfunction in chick cultured retinal cells.
The role of endogenous extracellular adenosine as a tonic modulator of the extracellular accumulation of excitatory amino acids (glutamate and aspartate) caused by metabolic inhibition was investigated in cultured retinal cells. The selective adenosine A2A receptor antagonist, 4-[2-[7-amino-2-(2-furyl)(1,2,4)-triazin-5-ylamino]-ethyl]ph enol (ZM241385) (50 nM), increased the release of glutamate (three- to four-fold) and of aspartate (nearly two-fold) upon iodoacetic acid-induced glycolysis inhibition, in the presence or in the absence of Ca2+. Blockade of tonic activation of A2A receptors by ZM241385 also increased (nearly two-fold) the ischemia-induced release of glutamate and aspartate. Furthermore, another selective A2A receptor antagonist, 5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5- c] pyrimidine (SCH58261), also increased the release of aspartate and glutamate by about two-fold in cells submitted to glycolysis inhibition. In contrast, the selective adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) (100 nM), did not significantly modify the extracellular accumulation of either glutamate or aspartate caused by inducers of chemical ischemia or glycolytic inhibitors. Inhibition of glycolysis also increased (about three-fold) the extracellular accumulation of GABA, which was virtually unchanged by ZM241385. Furthermore, the GABAA receptor antagonist, bicuculline (10 microM), only increased (nearly two-fold) the iodoacetic acid-induced Ca(2+)-dependent release of glutamate, whereas the GABAB receptor antagonist, 3-aminopropyl(diethoxymethyl) phosphinic acid, CGP35348 (100 microM), was devoid of effects on the extracellular accumulation of glutamate and aspartate. These results show that endogenous extracellular adenosine, which rises under conditions of inhibited glycolysis, tonically inhibits the extracellular accumulation of excitatory amino acid through the activation of A2A, but not A1, adenosine receptors, and this effect is independent of GABAA and GABAB functions in the cultured retinal cells.
Rego
A C
AC
Center for Neurosciences of Coimbra, University of Coimbra, Portugal.
Agostinho
P
P
Melo
J
J
Cunha
R A
RA
Oliveira
C R
CR
D000241:Adenosine / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001640:Bicuculline / Q000494:pharmacology; D002478:Cells, Cultured; D002642:Chick Embryo; D002851:Chromatography, High Pressure Liquid; D018846:Excitatory Amino Acids / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism*; D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D018698:Glutamic Acid / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D007511:Ischemia / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D012160:Retina / Q000378:metabolism*; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D018846:Excitatory Amino Acids; D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D009943:Organophosphorus Compounds; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D014227:Triazines; D014230:Triazoles; D014970:Xanthines; C097270:ZM 241385; D001224:Aspartic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C066430:CGP 35348; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine; D001640:Bicuculline