Antagonistic Interaction between Adenosine A_2AReceptors and Na⁺/K⁺-ATPase-α₂Controlling Glutamate Uptake in Astrocytes

<jats:p>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<jats:sup>+</jats:sup>/K<jats:sup>+</jats:sup>-ATPases (NKAs) and the α<jats:sub>2</jats:sub>subunit of NKA (NKA-α2) is actually linked to GLT-I to regulate astrocytic glutamate transport. We recently found that adenosine A<jats:sub>2A</jats:sub>receptors (A<jats:sub>2A</jats:sub>Rs), which control synaptic plasticity and neurodegeneration, regulate glutamate uptake through unknown mechanisms. Here we report that A<jats:sub>2A</jats:sub>R activation decreases NKA activity selectively in astrocytes to inhibit glutamate uptake. Furthermore, we found a physical association of A<jats:sub>2A</jats:sub>Rs with NKA-α2s in astrocytes, as gauged by coimmunoprecipitation and<jats:italic>in situ</jats:italic>proximity ligation assays, in the cerebral cortex and striatum, two brain regions where A<jats:sub>2A</jats:sub>Rs inhibit the astrocytic glutamate uptake. Moreover, the selective deletion of A<jats:sub>2A</jats:sub>Rs in astrocytes (using Gfa2-A<jats:sub>2A</jats:sub>R-KO mice) leads to a concurrent increase of both astrocytic glutamate uptake and NKA-α<jats:sub>2</jats:sub>levels and activity in the striatum and cortex. This coupling of astrocytic A<jats:sub>2A</jats:sub>Rs to the regulation of glutamate transport through modulation of NKA-α<jats:sub>2</jats:sub>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.</jats:p>