HOMEPRODUCTSSERVICESCOMPANYCONTACTFAQResearchDictionaryPharmaMobileSign Up FREE or Login

Role of Na+-K+-Cl- cotransport and Na+/Ca2+ exchange in mitochondrial dysfunction in astrocytes following in vitro ischemia.

Abstract
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.
AuthorsDouglas B Kintner, Jing Luo, Josiah Gerdts, Andy J Ballard, Gary E Shull, Dandan Sun
JournalAmerican journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 292 Issue 3 Pg. C1113-22 (Mar 2007) ISSN: 0363-6143 [Print] United States
PMID17035299 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Slc12a2 protein, mouse
  • Sodium-Calcium Exchanger
  • Sodium-Potassium-Chloride Symporters
  • Solute Carrier Family 12, Member 2
Topics
  • Animals
  • Astrocytes (metabolism)
  • Cell Hypoxia (physiology)
  • Cells, Cultured
  • Cerebral Cortex (physiology)
  • Membrane Potential, Mitochondrial (physiology)
  • Membrane Potentials (physiology)
  • Mice
  • Mice, Knockout
  • Mitochondria (physiology)
  • Reperfusion Injury (physiopathology)
  • Sodium-Calcium Exchanger (metabolism)
  • Sodium-Potassium-Chloride Symporters (metabolism)
  • Solute Carrier Family 12, Member 2

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!


Choose Username:
Email:
Password:
Verify Password: