title: Metabolic communication between astrocytes and neurons via bicarbonate-responsive soluble adenylyl cyclase.
abstract: Astrocytes are proposed to participate in brain energy metabolism by supplying substrates to neurons from their glycogen stores and from glycolysis. However, the molecules involved in metabolic sensing and the molecular pathways responsible for metabolic coupling between different cell types in the brain are not fully understood. Here we show that a recently cloned bicarbonate (HCO₃⁻) sensor, soluble adenylyl cyclase (sAC), is highly expressed in astrocytes and becomes activated in response to HCO₃⁻ entry via the electrogenic NaHCO₃ cotransporter (NBC). Activated sAC increases intracellular cAMP levels, causing glycogen breakdown, enhanced glycolysis, and the release of lactate into the extracellular space, which is subsequently taken up by neurons for use as an energy substrate. This process is recruited over a broad physiological range of [K⁺](ext) and also during aglycemic episodes, helping to maintain synaptic function. These data reveal a molecular pathway in astrocytes that is responsible for brain metabolic coupling to neurons.
authors.affiliation: Brain Research Centre, Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
authors.forename: Hyun B
authors.initials: HB
authors.lastname: Choi
authors.forename: Grant R J
authors.initials: GR
authors.lastname: Gordon
authors.forename: Ning
authors.initials: N
authors.lastname: Zhou
authors.forename: Chao
authors.initials: C
authors.lastname: Tai
authors.forename: Ravi L
authors.initials: RL
authors.lastname: Rungta
authors.forename: Jennifer
authors.initials: J
authors.lastname: Martinez
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Milner
authors.forename: Jae K
authors.initials: JK
authors.lastname: Ryu
authors.forename: James G
authors.initials: JG
authors.lastname: McLarnon
authors.forename: Martin
authors.initials: M
authors.lastname: Tresguerres
authors.forename: Lonny R
authors.initials: LR
authors.lastname: Levin
authors.forename: Jochen
authors.initials: J
authors.lastname: Buck
authors.forename: Brian A
authors.initials: BA
authors.lastname: MacVicar
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology* / Q000648:ultrastructure; D001639:Bicarbonates / Q000494:pharmacology*; D003373:Coumaric Acids / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005947:Glucose / Q000172:deficiency; D006003:Glycogen / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000378:metabolism; D016253:Microscopy, Immunoelectron; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology* / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D001639:Bicarbonates; D003373:Coumaric Acids; D005904:Glial Fibrillary Acidic Protein; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D027501:Monocarboxylic Acid Transporters; D010726:Phosphodiesterase Inhibitors; D026941:Sodium Channel Blockers; D049452:Green Fluorescent Proteins; C007175:alpha-cyano-4-hydroxycinnamate; D019344:Lactic Acid; D013779:Tetrodotoxin; D006003:Glycogen; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D005947:Glucose; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D011188:Potassium; D015056:1-Methyl-3-isobutylxanthine