A concerted role of Na+-K+-Cl- cotransporter and Na+/Ca2+ exchanger in ischemic damage

Jing Luo, Yanping Wang, Hai Chen, Douglas B. Kintner, Sam W. Cramer, Josiah K. Gerdts, Xinzhi Chen, Gary E. Shull, Kenneth D. Philipson, Dandan Sun

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29 Scopus citations


Na+-K+-Cl- cotransporter isoform 1 (NKCC1) and Na+/Ca2+ exchanger isoform 1 (NCX1) were expressed in cortical neurons. Three hours of oxygen and glucose deprivation (OGD) significantly increased expression of full-length NCX1 protein (∼116 kDa), which remained elevated during 1 to 21 h reoxygenation (REOX) and was accompanied with concurrent cleavage of NCX1. Na+/Ca2+ exchanger isoform 1 heterozygous (NCX1+/-) neurons with ∼50% less of NCX1 protein exhibited ∼64% reduction in NCX-mediated Ca2+ influx. Expression of NCX1 and NKCC1 proteins was reduced in double heterozygous (NCX1+/-/NKCC1+/-) neurons. NCX-mediated Ca2+ influx was nearly abolished in these neurons. Three-hour OGD and 21-h REOX caused ∼80% mortality rate in NCX1+/+ neurons and in NCX1 +/- neurons. In contrast, NKCC1+/- neurons exhibited ∼45% less cell death. The lowest mortality rate was found in NCX1 +/-/NKCC1+/- neurons (∼65% less neuronal death). The increased tolerance to ischemic damage was also observed in NCX1 +/-/NKCC1+/- brains after transient cerebral ischemia. NCX1+/-/NKCC1+/- mice had a significantly reduced infarct volume at 24 and 72 h reperfusion. In conclusion, these data suggest that NKCC1 in conjunction with NCX1 plays a role in reperfusion-induced brain injury after ischemia.

Original languageEnglish (US)
Pages (from-to)737-746
Number of pages10
JournalJournal of Cerebral Blood Flow and Metabolism
Issue number4
StatePublished - Apr 2008


  • Ca overload
  • Focal ischemia
  • Infarction
  • KB-R7943
  • Neuronal death


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