PMID- 17035299
OWN - NLM
STAT- MEDLINE
DCOM- 20070424
LR  - 20220224
IS  - 0363-6143 (Print)
IS  - 0363-6143 (Linking)
VI  - 292
IP  - 3
DP  - 2007 Mar
TI  - Role of Na+-K+-Cl- cotransport and Na+/Ca2+ exchange in mitochondrial dysfunction 
      in astrocytes following in vitro ischemia.
PG  - C1113-22
AB  - Na(+)-K(+)-Cl(-) cotransporter isoform 1 (NKCC1) and reverse mode operation of 
      the Na(+)/Ca(2+) exchanger (NCX) contribute to intracellular Na(+) and Ca(2+) 
      overload in astrocytes following oxygen-glucose deprivation (OGD) and 
      reoxygenation (REOX). Here, we further investigated whether NKCC1 and NCX play a 
      role in mitochondrial Ca(2+) (Ca(m)(2+)) overload and dysfunction. OGD/REOX 
      caused a doubling of mitochondrial-releasable Ca(2+) (P < 0.05). When NKCC1 was 
      inhibited with bumetanide, the mitochondrial-releasable Ca(2+) was reduced by 
      approximately 42% (P < 0.05). Genetic ablation of NKCC1 also reduced Ca(m)(2+) 
      accumulation. Moreover, OGD/REOX in NKCC1(+/+) astrocytes caused dissipation of 
      the mitochondrial membrane potential (Psi(m)) to 42 +/- 3% of controls. In 
      contrast, when NKCC1 was inhibited with bumetanide, depolarization of Psi(m) was 
      attenuated significantly (66 +/- 10% of controls, P < 0.05). Cells were also 
      subjected to severe in vitro hypoxia by superfusion with a hypoxic, acidic, 
      ion-shifted Ringer buffer (HAIR). HAIR/REOX triggered a secondary, sustained rise 
      in intracellular Ca(2+) that was attenuated by reversal NCX inhibitor KB-R7943. 
      The hypoxia-mediated increase in Ca(m)(2+) was accompanied by loss of Psi(m) and 
      cytochrome c release in NKCC1(+/+) astrocytes. Bumetanide or genetic ablation of 
      NKCC1 attenuated mitochondrial dysfunction and astrocyte death following 
      ischemia. Our study suggests that NKCC1 acting in concert with NCX causes a 
      perturbation of Ca(m)(2+) homeostasis and mitochondrial dysfunction and cell 
      death following in vitro ischemia.
FAU - Kintner, Douglas B
AU  - Kintner DB
AD  - Dept. of Neurological Surgery, University of Wisconsin School of Medicine, 
      Madison, WI 53792, USA.
FAU - Luo, Jing
AU  - Luo J
FAU - Gerdts, Josiah
AU  - Gerdts J
FAU - Ballard, Andy J
AU  - Ballard AJ
FAU - Shull, Gary E
AU  - Shull GE
FAU - Sun, Dandan
AU  - Sun D
LA  - eng
GR  - R01HL-61974/HL/NHLBI NIH HHS/United States
GR  - R01NS-38118/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20061011
PL  - United States
TA  - Am J Physiol Cell Physiol
JT  - American journal of physiology. Cell physiology
JID - 100901225
RN  - 0 (Slc12a2 protein, mouse)
RN  - 0 (Sodium-Calcium Exchanger)
RN  - 0 (Sodium-Potassium-Chloride Symporters)
RN  - 0 (Solute Carrier Family 12, Member 2)
SB  - IM
MH  - Animals
MH  - Astrocytes/*metabolism
MH  - Cell Hypoxia/physiology
MH  - Cells, Cultured
MH  - Cerebral Cortex/*physiology
MH  - Membrane Potential, Mitochondrial/physiology
MH  - Membrane Potentials/physiology
MH  - Mice
MH  - Mice, Knockout
MH  - Mitochondria/*physiology
MH  - Reperfusion Injury/physiopathology
MH  - Sodium-Calcium Exchanger/*metabolism
MH  - Sodium-Potassium-Chloride Symporters/*metabolism
MH  - Solute Carrier Family 12, Member 2
EDAT- 2006/10/13 09:00
MHDA- 2007/04/25 09:00
CRDT- 2006/10/13 09:00
PHST- 2006/10/13 09:00 [pubmed]
PHST- 2007/04/25 09:00 [medline]
PHST- 2006/10/13 09:00 [entrez]
AID - 00412.2006 [pii]
AID - 10.1152/ajpcell.00412.2006 [doi]
PST - ppublish
SO  - Am J Physiol Cell Physiol. 2007 Mar;292(3):C1113-22. doi: 
      10.1152/ajpcell.00412.2006. Epub 2006 Oct 11.