title: GLUT4 Mobilization Supports Energetic Demands of Active Synapses.
abstract: The brain is highly sensitive to proper fuel availability as evidenced by the rapid decline in neuronal function during ischemic attacks and acute severe hypoglycemia. We previously showed that sustained presynaptic function requires activity-driven glycolysis. Here, we provide strong evidence that during action potential (AP) firing, nerve terminals rely on the glucose transporter GLUT4 as a glycolytic regulatory system to meet the activity-driven increase in energy demands. Activity at synapses triggers insertion of GLUT4 into the axonal plasma membrane driven by activation of the metabolic sensor AMP kinase. Furthermore, we show that genetic ablation of GLUT4 leads to an arrest of synaptic vesicle recycling during sustained AP firing, similar to what is observed during acute glucose deprivation. The reliance on this biochemical regulatory system for "exercising" synapses is reminiscent of that occurring in exercising muscle to sustain cellular function and identifies nerve terminals as critical sites of proper metabolic control.
authors.affiliation: Department of Biochemistry, Weill Cornell Medicine, New York, NY 10021, USA.
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Ashrafi
authors.affiliation: Laboratory of Brain Development and Repair, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Zhuhao
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, Weill Cornell Medicine, New York, NY 10021, USA; Laboratory of Brain Development and Repair, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Farrell
authors.affiliation: Department of Biochemistry, Weill Cornell Medicine, New York, NY 10021, USA. Electronic address: taryan@med.cornell.edu.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Ryan
mesh_terms: D000200:Action Potentials; D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D006019:Glycolysis; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D007150:Immunohistochemistry; D009474:Neurons / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000378:metabolism; D013572:Synaptic Vesicles / Q000378:metabolism*
chemical_list: D051275:Glucose Transporter Type 4; C495694:Slc2a4 protein, rat; D000263:Adenylate Kinase
keywords: GLUT4; glucose transport; glycolysis; neuronal metabolism; presynaptic function; vesicle cycle