title: Tissue-type plasminogen activator regulates the neuronal uptake of glucose in the ischemic brain.
abstract: The ability to sense and adapt to hypoxic conditions plays a pivotal role in neuronal survival. Hypoxia induces the release of tissue-type plasminogen activator (tPA) from cerebral cortical neurons. We found that the release of neuronal tPA or treatment with recombinant tPA promotes cell survival in cerebral cortical neurons previously exposed to hypoxic conditions in vitro or experimental cerebral ischemia in vivo. Our studies using liquid chromatography and tandem mass spectrometry revealed that tPA activates the mammalian target of rapamycin (mTOR) pathway, which adapts cellular processes to the availability of energy and metabolic resources. We found that mTOR activation leads to accumulation of the hypoxia-inducible factor-1α (HIF-1α) and induction and recruitment to the cell membrane of the HIF-1α-regulated neuronal transporter of glucose GLUT3. Accordingly, in vivo positron emission tomography studies with 18-fluorodeoxyglucose in mice overexpressing tPA in neurons show that neuronal tPA induces the uptake of glucose in the ischemic brain and that this effect is associated with a decrease in the volume of the ischemic lesion and improved neurological outcome following the induction of ischemic stroke. Our data indicate that tPA activates a cell signaling pathway that allows neurons to sense and adapt to oxygen and glucose deprivation.
authors: Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: Fang
authors: F
authors: Wu
authors: Jialing
authors: J
authors: Wu
authors: Andrew D
authors: AD
authors: Nicholson
authors: Ramiro
authors: R
authors: Echeverry
authors: Woldeab B
authors: WB
authors: Haile
authors: Marcela
authors: M
authors: Catano
authors: Jie
authors: J
authors: An
authors: Andrew K
authors: AK
authors: Lee
authors: Duc
authors: D
authors: Duong
authors: Eric B
authors: EB
authors: Dammer
authors: Nicholas T
authors: NT
authors: Seyfried
authors: Frank C
authors: FC
authors: Tong
authors: John R
authors: JR
authors: Votaw
authors: Robert L
authors: RL
authors: Medcalf
authors: Manuel
authors: M
authors: Yepes
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
chemical_list: D005343:Fibrinolytic Agents; D058570:TOR Serine-Threonine Kinases; D010959:Tissue Plasminogen Activator; D005947:Glucose