title: Activity-dependent regulation of surface glucose transporter-3.
abstract: Glucose transporter 3 (GLUT3) is the main facilitative glucose transporter in neurons. Glucose provides neurons with a critical energy source for neuronal activity. However, the mechanism by which neuronal activity controls glucose influx via GLUT3 is unknown. We investigated the influence of synaptic stimulation on GLUT3 surface expression and glucose import in primary cultured cortical and hippocampal neurons. Synaptic activity increased surface expression of GLUT3 leading to an elevation of intracellular glucose. The effect was blocked by NMDA receptor (NMDAR) and neuronal nitric oxide synthase (nNOS) inhibition. The Akt inhibitor I (Akt-I) blocked NMDAR-induced GLUT3 surface expression while a nNOS-phosphomimetic mutant (S1412D) enhanced GLUT3 expression at cell surface. These results suggest that NMDAR/Akt-dependent nNOS phosphorylation is coupled to GLUT3 trafficking. We demonstrated that activation of cGMP-dependent protein kinase (cGK) increased the surface expression of GLUT3, which was repressed by Rp-8-pCPT-cGMPS, a potent cell-permeable inhibitor of cGKs. These studies characterize the molecular basis for activity-dependent increases in surface GLUT3 after stimulation of the NMDARs. NMDAR-induced increase in surface GLUT3 represents a novel pathway for control of energy supply during neuronal activity that is critical for maintaining glucose homeostasis during neuronal transmission.
authors.affiliation: Department of Biochemistry, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Jainne M
authors.initials: JM
authors.lastname: Ferreira
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Burnett
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Rameau
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D019921:Biotinylation / Q000379:methods; D002540:Cerebral Cortex / Q000166:cytology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D000076122:Disks Large Homolog 4 Protein; D004285:Dogs; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051274:Glucose Transporter Type 3 / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006601:Hexoses / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000235:genetics; D026902:Potassium Channel Blockers / Q000494:pharmacology; D021381:Protein Transport / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D013873:Thionucleotides / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C090860:8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D058787:GABA-A Receptor Antagonists; D051274:Glucose Transporter Type 3; D006601:Hexoses; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C409466:NR1 NMDA receptor; D026902:Potassium Channel Blockers; D016194:Receptors, N-Methyl-D-Aspartate; D013873:Thionucleotides; D049452:Green Fluorescent Proteins; C083763:8-bromoguanosino-3',5'-cyclic monophosphorothioate; D009569:Nitric Oxide; D012694:Serine; C056639:2-amino-5-phosphopentanoic acid; D015761:4-Aminopyridine; D052248:Nitric Oxide Synthase Type I; D006152:Cyclic GMP; D014633:Valine; D001640:Bicuculline