title: Adenosine A2B receptor activation stimulates glucose uptake in the mouse forebrain.
abstract: ATP consumption during intense neuronal activity leads to peaks of both extracellular adenosine levels and increased glucose uptake in the brain. Here, we investigated the hypothesis that the activation of the low-affinity adenosine receptor, the A2B receptor (A(2B)R), promotes glucose uptake in neurons and astrocytes, thereby linking brain activity with energy metabolism. To this end, we mapped the spatiotemporal accumulation of the fluorescent-labelled deoxyglucose, 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG), in superfused acute hippocampal slices of C57Bl/6j mice. Bath application of the A(2B)R agonist BAY606583 (300 nM) triggered an immediate and stable (>10 min) increase of the velocity of 2-NBDG accumulation throughout hippocampal slices. This was abolished with the pretreatment with the selective A(2B)R antagonist, MRS1754 (200 nM), and was also absent in A(2B)R null-mutant mice. In mouse primary astrocytic or neuronal cultures, BAY606583 similarly increased (3)H-deoxyglucose uptake in the following 20 min incubation period, which was again abolished by a pretreatment with MRS1754. Finally, incubation of hippocampal, frontocortical, or striatal slices of C57Bl/6j mice at 37 °C, with either MRS1754 (200 nM) or adenosine deaminase (3 U/mL) significantly reduced glucose uptake. Furthermore, A(2B)R blockade diminished newly synthesized glycogen content and at least in the striatum, increased lactate release. In conclusion, we report here that A(2B)R activation is associated with an instant and tonic increase of glucose transport into neurons and astrocytes in the mouse brain. These prompt further investigations to evaluate the clinical potential of this novel glucoregulator mechanism.
authors.affiliation: CNC, Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504, Coimbra, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Lemos
authors.affiliation: CNC, Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504, Coimbra, Portugal.
authors.forename: Bárbara S
authors.initials: BS
authors.lastname: Pinheiro
authors.affiliation: CNC, Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504, Coimbra, Portugal.
authors.forename: Rui O
authors.initials: RO
authors.lastname: Beleza
authors.affiliation: CNC, Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504, Coimbra, Portugal.
authors.forename: Joana M
authors.initials: JM
authors.lastname: Marques
authors.affiliation: CNC, Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504, Coimbra, Portugal.|Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal.
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Rodrigues
authors.affiliation: CNC, Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504, Coimbra, Portugal.|FMUC, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Cunha
authors.affiliation: CNC, Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504, Coimbra, Portugal.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rial
authors.affiliation: CNC, Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504, Coimbra, Portugal. akofalvi@uc.pt.|Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal. akofalvi@uc.pt.
authors.forename: Attila
authors.identifier: http://orcid.org/0000-0001-6910-9707
authors.initials: A
authors.lastname: Köfalvi
mesh_terms: D009327:4-Chloro-7-nitrobenzofurazan / Q000031:analogs & derivatives* / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism*; D043704:Receptor, Adenosine A2B / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*
chemical_list: D058908:Adenosine A2 Receptor Agonists; D043704:Receptor, Adenosine A2B; D019344:Lactic Acid; D003847:Deoxyglucose; D009327:4-Chloro-7-nitrobenzofurazan; D005947:Glucose; C098340:2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose
keywords: 2-NBDG; Adenosine A2B receptor; Frontal cortex; Glucose uptake; Glycogen; Hippocampus; Lactate; Striatum