PMID- 15569671
OWN - NLM
STAT- MEDLINE
DCOM- 20050322
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 280
IP  - 5
DP  - 2005 Feb 4
TI  - Hydrogen peroxide potentiates volume-sensitive excitatory amino acid release via 
      a mechanism involving Ca2+/calmodulin-dependent protein kinase II.
PG  - 3548-54
AB  - Excessive excitatory amino acid (EAA) release in cerebral ischemia is a major 
      mechanism responsible for neuronal damage and death. A substantial fraction of 
      ischemic EAA release occurs via volume-regulated anion channels (VRACs). Hydrogen 
      peroxide (H2O2), which is abundantly produced during ischemia and reperfusion, 
      activates a number of protein kinases critical for VRAC functioning and has 
      recently been reported to activate VRACs. In the present study, we explored the 
      effects of H2O2 on volume-dependent EAA release in cultured astrocytes, measured 
      as the release of preloaded D-[3H]aspartate. 100-1,000 microm H2O2 enhanced 
      swelling-induced EAA release by approximately 2.5-3-fold (EC50 approximately 10 
      microM). The VRAC blockers ATP, phloretin, and 
      5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB) potently inhibited both control 
      swelling-induced and the H2O2-potentiated release, suggesting a role for VRACs. 
      The H2O2-induced component of EAA release was attenuated by the Ca2+ chelator 
      1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester 
      (BAPTA-AM) and completely eliminated by the calmodulin antagonists 
      trifluoperazine and W-7 and the Ca2+/calmodulin-dependent protein kinase II 
      (CaMKII) inhibitor KN-93. Inhibitors of tyrosine kinases, protein kinase C, and 
      the myosin light chain kinase were ineffective in blocking the H2O2 response. 
      H2O2 treatment of swollen astrocytes, but not swelling alone, resulted in CaMKII 
      activation that was inhibited by KN-93, as determined by a phospho-Thr286 CaMKII 
      antibody. These data demonstrate that H2O2 strongly up-regulates astrocytic 
      volume-sensitive EAA release via a CaMKII-dependent mechanism and in this way may 
      potently promote pathological EAA release and brain damage in ischemia.
FAU - Haskew-Layton, Renee E
AU  - Haskew-Layton RE
AD  - Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, 
      New York 12208, USA.
FAU - Mongin, Alexander A
AU  - Mongin AA
FAU - Kimelberg, Harold K
AU  - Kimelberg HK
LA  - eng
GR  - F31 NS046961/NS/NINDS NIH HHS/United States
GR  - R01 NS035205/NS/NINDS NIH HHS/United States
GR  - F31-NS46961/NS/NINDS NIH HHS/United States
GR  - R01-NS35205/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20041129
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Amino Acids)
RN  - 0 (Anions)
RN  - 0 (Ion Channels)
RN  - 0 (Oxidants)
RN  - 10028-17-8 (Tritium)
RN  - 30KYC7MIAI (Aspartic Acid)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
SB  - IM
MH  - Amino Acids/*metabolism
MH  - Animals
MH  - Anions/metabolism
MH  - Aspartic Acid/pharmacokinetics
MH  - Astrocytes/cytology/drug effects/*metabolism
MH  - Calcium-Calmodulin-Dependent Protein Kinase Type 2
MH  - Calcium-Calmodulin-Dependent Protein Kinases/*metabolism
MH  - Cells, Cultured
MH  - Glutamic Acid/pharmacokinetics
MH  - Hydrogen Peroxide/*pharmacology
MH  - Ion Channels/metabolism
MH  - Oxidants/*pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction/drug effects/physiology
MH  - Tritium
EDAT- 2004/12/01 09:00
MHDA- 2005/03/23 09:00
CRDT- 2004/12/01 09:00
PHST- 2004/12/01 09:00 [pubmed]
PHST- 2005/03/23 09:00 [medline]
PHST- 2004/12/01 09:00 [entrez]
AID - S0021-9258(20)76222-8 [pii]
AID - 10.1074/jbc.M409803200 [doi]
PST - ppublish
SO  - J Biol Chem. 2005 Feb 4;280(5):3548-54. doi: 10.1074/jbc.M409803200. Epub 2004 
      Nov 29.