title: Antagonistic interaction between adenosine A2A receptors and Na+/K+-ATPase-α2 controlling glutamate uptake in astrocytes.
abstract: 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 α2 subunit of NKA (NKA-α2) is actually linked to GLT-I to regulate astrocytic glutamate transport. We recently found that adenosine A2A receptors (A2ARs), which control synaptic plasticity and neurodegeneration, regulate glutamate uptake through unknown mechanisms. Here we report that A2AR activation decreases NKA activity selectively in astrocytes to inhibit glutamate uptake. Furthermore, we found a physical association of A2ARs with NKA-α2s in astrocytes, as gauged by coimmunoprecipitation and in situ proximity ligation assays, in the cerebral cortex and striatum, two brain regions where A2ARs inhibit the astrocytic glutamate uptake. Moreover, the selective deletion of A2ARs in astrocytes (using Gfa2-A2AR-KO mice) leads to a concurrent increase of both astrocytic glutamate uptake and NKA-α2 levels and activity in the striatum and cortex. This coupling of astrocytic A2ARs to the regulation of glutamate transport through modulation of NKA-α2 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.
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118, CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal, and FMUC-Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal.
authors.forename: Marco
authors.initials: M
authors.lastname: Matos
authors.forename: Elisabete
authors.initials: E
authors.lastname: Augusto
authors.forename: Paula
authors.initials: P
authors.lastname: Agostinho
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Cunha
authors.forename: Jiang-Fan
authors.initials: JF
authors.lastname: Chen
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects* / Q000648:ultrastructure; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism*; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010042:Ouabain / Q000494:pharmacology; D010627:Phenethylamines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000172:deficiency / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D014316:Tritium / Q000378:metabolism
chemical_list: C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D005904:Glial Fibrillary Acidic Protein; D010627:Phenethylamines; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D014230:Triazoles; D014316:Tritium; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D001224:Aspartic Acid; D018698:Glutamic Acid; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase; D000241:Adenosine