Antagonistic Interaction between Adenosine A2A Receptors and Na+/K+-ATPase-α2 Controlling Glutamate Uptake in Astrocytes

Astrocytic glutamate transporter-1 (GLT-I) is critical to control the bulk of glutamate uptake and, thus, to regulate synaptic plasticity and excitotoxicity. GLT-I glutamate uptake is driven by the sodium gradient implemented by Na+/K+-ATPases (NKAs) and the alpha(2) subunit of NKA (NKA-alpha 2) is actually linked to GLT-I to regulate astrocytic glutamate transport. We recently found that adenosine A(2A) receptors (A(2A)Rs), which control synaptic plasticity and neurodegeneration, regulate glutamate uptake through unknown mechanisms. Here we report that A(2A) R activation decreases NKA activity selectively in astrocytes to inhibit glutamate uptake. Furthermore, we found a physical association of A(2A)Rs with NKA-alpha 2s in astrocytes, as gauged by coimmunoprecipitation and in situ proximity ligation assays, in the cerebral cortex and striatum, two brain regions where A(2A)Rs inhibit the astrocytic glutamate uptake. Moreover, the selective deletion of A(2A)Rs in astrocytes (using Gfa2-A(2A)R-KO mice) leads to a concurrent increase of both astrocytic glutamate uptake andNKA-alpha(2) levels and activity in the striatum and cortex. This coupling of astrocytic A(2A)Rs to the regulation of glutamate transport through modulation of NKA-alpha(2) activity provides a novel mechanism linking neuronal activity to ion homeostasis controlling glutamatergic activity, all of which are processes intricately associated with the etiology of several brain diseases.