Hypoxia-induced desensitization and internalization of adenosine A1 receptors in the rat hippocampus

Activation of A(1) adenosine receptors is important for both the neuromodulatory and neuroprotective effects of adenosine. However, short periods of global ischemia decrease A(1) adenosine receptor density in the brain and it is not known if a parallel loss of functional efficiency of A(1) adenosine receptors occurs. We now tested if hypoxia leads to changes in the density and efficiency of A(1) 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 mu M. After hypoxia (95% N-2 and 5% CO2, for 60 min) and reoxygenation (30 min), the EC50 increased to 0.73 mu M. This EC50 shift was prevented by the presence of the A(1) adenosine receptor antagonist 8-phenyltheophyline, but not by the A(2A)R antagonist 7-(2-phenylethyi)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 A(1) adenosine receptors was not paralleled by a global change of A(1) adenosine receptor density or affinity (as evaluated by the binding parameters obtained in nerve terminal membranes). However, the density of biotinylated A(1) adenosine receptors at the plasma membrane of nerve terminals was reduced by 30% upon hypoxia/reoxygenation, in a manner prevented by the A(1) adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine and mimicked by prolonged (60 min) supra-maximal activation of A(1) adenosine receptors with 2-chloroadenosine (10 mu M). These results indicate that hypoxia leads to a rapid (<90 min) homologous desensitization of A(1) adenosine receptor-mediated inhibition of synaptic transmission that is likely due to an internalization of A(1) adenosine receptors in nerve terminals. (C) 2005 Published by Elsevier Ltd on behalf of IBRO.