Hypoxia-induced desensitization and internalization of adenosine A1 receptors in the rat hippocampus.
Activation of A1 adenosine receptors is important for both the neuromodulatory and neuroprotective effects of adenosine. However, short periods of global ischemia decrease A1 adenosine receptor density in the brain and it is not known if a parallel loss of functional efficiency of A1 adenosine receptors occurs. We now tested if hypoxia leads to changes in the density and efficiency of A1 adenosine receptors to inhibit excitatory synaptic transmission in rat hippocampal slices. In control conditions, the adenosine analog 2-chloroadenosine, inhibited field excitatory post-synaptic potentials with an EC50 of 0.23 microM. After hypoxia (95% N2 and 5% CO2, for 60 min) and reoxygenation (30 min), the EC50 increased to 0.73 microM. This EC50 shift was prevented by the presence of the A1 adenosine receptor antagonist 8-phenyltheophyline, but not by the A(2A)R antagonist 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c] pyrimidine, during the hypoxic period. This decreased efficiency of A1 adenosine receptors was not paralleled by a global change of A1 adenosine receptor density or affinity (as evaluated by the binding parameters obtained in nerve terminal membranes). However, the density of biotinylated A1 adenosine receptors at the plasma membrane of nerve terminals was reduced by 30% upon hypoxia/reoxygenation, in a manner prevented by the A1 adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine and mimicked by prolonged (60 min) supra-maximal activation of A1 adenosine receptors with 2-chloroadenosine (10 microM). These results indicate that hypoxia leads to a rapid (<90 min) homologous desensitization of A1 adenosine receptor-mediated inhibition of synaptic transmission that is likely due to an internalization of A1 adenosine receptors in nerve terminals.
Coelho
J E
JE
Laboratory of Neurosciences, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, 1649-028 Lisboa, Portugal.
Rebola
N
N
Fragata
I
I
Ribeiro
J A
JA
de Mendonça
A
A
Cunha
R A
RA
D015762:2-Chloroadenosine / Q000494:pharmacology; D000241:Adenosine / Q000378:metabolism; D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D004195:Disease Models, Animal; D004705:Endocytosis / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D017729:Presynaptic Terminals / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D058916:Adenosine A1 Receptor Antagonists; D043682:Receptor, Adenosine A1; D014970:Xanthines; D015762:2-Chloroadenosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D013806:Theophylline; C028322:8-phenyltheophylline; D000241:Adenosine