Modulation of the Rat Hippocampal Dinucleotide Receptor by Adenosine Receptor Activation

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Abstract
Diadenosine pentaphosphate (Ap5A) and ATP stimulate an intracellular free calcium concentration ([Ca2+]I) increase in rat hippocampal synaptosomes via different receptors as demonstrated by the lack of cross-desensitization between Ap5A and ATP responses. The ATP response was inhibited by P2 receptor antagonists and not by the dinucleotide receptor antagonist, diinosine pentaphosphate (Ip5I). In contrast, the Ap5A response was inhibited by Ip5I but not by P2 receptor antagonists. Studies in single hippocampal synaptic terminals showed that 31% of them responded to Ap5A by a [Ca2+]i increase. Adenosine receptors (A1, A2A, and A3) were also present in isolated terminals as demonstrated by immunohistochemistry. The activation of A1 or A2A receptors by specific agonists changed the sigmoid concentration-response curve for Ap5A (EC50 = 33.5 ± 4.5 μM) into biphasic curves. When the high-affinity adenosine receptors A1 or A2A were activated, the Ap5A dose-response curves showed a high-affinity component with EC50 values of 41.1 ± 1.9 pM and 99.9 ± 10.2 nM, respectively. The low-affinity component showed EC50values of 17.1 ± 0.8 and 21.6 ± 1.4 μM for A1and A2A receptor activation, respectively. However, the adenosine A3 receptor activation induced a right shift of the dinucleotide concentration-response curve, showing an EC50 value of 331.4 ± 54.6 μM. In addition, in the presence of the A2A agonist, the Ap5A calcium influx responses were increased up to 300% of the control values. These results clearly demonstrate that the activation of presynaptic adenosine receptors is able to modulate the dinucleotide response in hippocampal nerve terminals.