title: Glucose deprivation reversibly down-regulates tissue plasminogen activator via proteasomal degradation in rat primary astrocytes.
abstract: OBJECTIVE
  Tissue plasminogen activator (tPA) is an essential neuromodulator whose involvement in multiple functions such as synaptic plasticity, cytokine-like immune function and regulation of cell survival mandates rapid and tight tPA regulation in the brain. We investigated the possibility that a transient metabolic challenge induced by glucose deprivation may affect tPA activity in rat primary astrocytes, the main cell type responsible for metabolic regulation in the CNS.
  
  
  METHODS
  Rat primary astrocytes were incubated in serum-free DMEM without glucose. Casein zymography was used to determine tPA activity, and tPA mRNA was measured by RT-PCR. The signaling pathways regulating tPA activity were identified by Western blotting.
  
  
  RESULTS
  Glucose deprivation rapidly down-regulated the activity of tPA without affecting its mRNA level in rat primary astrocytes; this effect was mimicked by translational inhibitors. The down-regulation of tPA was accompanied by increased tPA degradation, which may be modulated by a proteasome-dependent degradation pathway. Glucose deprivation induced activation of PI3K-Akt-GSK3β, p38 and AMPK, and inhibition of these pathways using LY294002, SB203580 and compound C significantly inhibited glucose deprivation-induced tPA down-regulation, demonstrating the essential role of these pathways in tPA regulation in glucose-deprived astrocytes.
  
  
  CONCLUSIONS
  Rapid and reversible regulation of tPA activity in rat primary astrocytes during metabolic crisis may minimize energy-requiring neurologic processes in stressed situations. This effect may thereby increase the opportunity to invest cellular resources in cell survival and may allow rapid re-establishment of normal cellular function after the crisis.
authors.affiliation: Department of Neuroscience, School of Medicine, Konkuk University, Seoul, Republic of Korea.
authors.forename: Kyu Suk
authors.initials: KS
authors.lastname: Cho
authors.forename: So Hyun
authors.initials: SH
authors.lastname: Joo
authors.forename: Chang Soon
authors.initials: CS
authors.lastname: Choi
authors.forename: Ki Chan
authors.initials: KC
authors.lastname: Kim
authors.forename: Hyun Myung
authors.initials: HM
authors.lastname: Ko
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Park
authors.forename: Pitna
authors.initials: P
authors.lastname: Kim
authors.forename: Jun
authors.initials: J
authors.lastname: Hur
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Geon Ho
authors.initials: GH
authors.lastname: Bahn
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Ryu
authors.forename: Jongmin
authors.initials: J
authors.lastname: Lee
authors.forename: Seol-Heui
authors.initials: SH
authors.lastname: Han
authors.forename: Kyoung Ja
authors.initials: KJ
authors.lastname: Kwon
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Shin
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D015153:Blotting, Western; D002867:Chromones / Q000494:pharmacology; D015536:Down-Regulation; D005947:Glucose / Q000172:deficiency*; D007093:Imidazoles / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
chemical_list: D002867:Chromones; D007093:Imidazoles; D009025:Morpholines; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D012333:RNA, Messenger; C516138:dorsomorphin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D010959:Tissue Plasminogen Activator; D046988:Proteasome Endopeptidase Complex; D005947:Glucose; C093642:SB 203580