Nucleoside diphosphate kinase B knock-out mice have impaired activation of the K+ channel KCa3.1, resulting in defective T cell activation

J Biol Chem. 2010 Dec 10;285(50):38765-71. doi: 10.1074/jbc.M110.168070. Epub 2010 Sep 30.


Nucleoside diphosphate kinases (NDPKs) are encoded by the Nme (non-metastatic cell) gene family. Although they comprise a family of 10 genes, NDPK-A and -B are ubiquitously expressed and account for most of the NDPK activity. We previously showed that NDPK-B activates the K(+) channel KCa3.1 via histidine phosphorylation of the C terminus of KCa3.1, which is required for T cell receptor-stimulated Ca(2+) flux and proliferation of activated naive human CD4 T cells. We now report the phenotype of NDPK-B(-/-) mice. NDPK-B(-/-) mice are phenotypically normal at birth with a normal life span. Although T and B cell development is normal in NDPK-B(-/-) mice, KCa3.1 channel activity and cytokine production are markedly defective in T helper 1 (Th1) and Th2 cells, whereas Th17 function is normal. These findings phenocopy studies in the same cells isolated from KCa3.1(-/-) mice and thereby support genetically that NDPK-B functions upstream of KCa3.1. NDPK-A and -B have been linked to an astonishing array of disparate cellular and biochemical functions, few of which have been confirmed in vivo in physiological relevant systems. NDPK-B(-/-) mice will be an essential tool with which to definitively address the biological functions of NDPK-B. Our finding that NDPK-B is required for activation of Th1 and Th2 CD4 T cells, together with the normal overall phenotype of NDPK-B(-/-) mice, suggests that specific pharmacological inhibitors of NDPK-B may provide new opportunities to treat Th1- and Th2-mediated autoimmune diseases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / metabolism
  • Flow Cytometry
  • Histidine Kinase
  • Humans
  • Intermediate-Conductance Calcium-Activated Potassium Channels / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • NM23 Nucleoside Diphosphate Kinases / genetics*
  • Patch-Clamp Techniques
  • Potassium / chemistry*
  • Protein Kinases / metabolism
  • Signal Transduction
  • T-Lymphocytes / cytology
  • T-Lymphocytes / metabolism*


  • Intermediate-Conductance Calcium-Activated Potassium Channels
  • Kcnn4 protein, mouse
  • NM23 Nucleoside Diphosphate Kinases
  • Protein Kinases
  • Histidine Kinase
  • Potassium