Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: different roles, different sources and different receptors.

Adenosine exerts two parallel modulatory roles in the CNS, acting as a homeostatic modulator and also as a neuromodulator at the synaptic level. We will present evidence to suggest that these two different modulatory roles are fulfilled by extracellular adenosine originated from different metabolic sources, and involve receptors with different sub-cellular localisation. It is widely accepted that adenosine is an inhibitory modulator in the CNS, a notion that stems from the preponderant role of inhibitory adenosine A(1) receptors in defining the homeostatic modulatory role of adenosine. However, we will review recent data that suggests that the synaptically localised neuromodulatory role of adenosine depend on a balanced activation of inhibitory A(1) receptors and mostly facilitatory A(2A) receptors. This balanced activation of A(1) and A(2A) adenosine receptors depends not only on the transient levels of extracellular adenosine, but also on the direct interaction between A(1) and A(2A) receptors, which control each other's action.