Regulation of erythrocyte Na/K/2Cl cotransport by an oxygen-switched kinase cascade

Suilan Zheng, Nathan A. Krump, Mary M. McKenna, Yen Hsing Li, Anke Hannemann, Lisa J. Garrett, John S. Gibson, David M. Bodine, Philip S. Low

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Many erythrocyte processes and pathways, including glycolysis, the pentose phosphate pathway (PPP), KCl cotransport, ATP release, Na/K-ATPase activity, ankyrin– band 3 interactions, and nitric oxide (NO) release, are regulated by changes in O2 pressure that occur as a red blood cell (RBC) transits between the lungs and tissues. The O2 dependence of glycolysis, PPP, and ankyrin– band 3 interactions (affecting RBC rheology) are controlled by O2-dependent competition between deoxyhemoglobin (deoxyHb), but not oxyhemoglobin (oxyHb), and other proteins for band 3. We undertook the present study to determine whether the O2 dependence of Na/K/2Cl cotransport (catalyzed by Na/K/2Cl cotransporter 1 [NKCC1]) might similarly originate from competition between deoxyHb and a protein involved in NKCC1 regulation for a common binding site on band 3. Using three transgenic mouse strains having mutated deoxyhemoglobin-binding sites on band 3, we found that docking of deoxyhemoglobin at the N terminus of band 3 displaces the protein with no lysine kinase 1 (WNK1) from its overlapping binding site on band 3. This displacement enabled WNK1 to phosphorylate oxidative stress-responsive kinase 1 (OSR1), which, in turn, phosphorylated and activated NKCC1. Under normal solution conditions, the NKCC1 activation increased RBC volume and thereby induced changes in RBC rheology. Because the deoxyhemoglobin-mediated WNK1 displacement from band 3 in this O2 regulation pathway may also occur in the regulation of other O2-regulated ion transporters, we hypothesize that the NKCC1-mediated regulatory mechanism may represent a general pattern of O2 modulation of ion transporters in erythrocytes.

Original languageEnglish (US)
Pages (from-to)2519-2528
Number of pages10
JournalJournal of Biological Chemistry
Issue number7
StatePublished - Feb 15 2019

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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