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KCNN4  -  potassium channel, calcium activated...

Homo sapiens

Synonyms: IK, IK1, IKCA1, IKCa1, Intermediate conductance calcium-activated potassium channel protein 4, ...
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Disease relevance of KCNN4


High impact information on KCNN4

  • Potassium currents in the myocardium can be classified into one of two general categories: 1) inward rectifying currents such as IK1, IKACh, and IKATP; and 2) primarily voltage-gated currents such as IKs, IKr, IKp, IKur, and Ito [6].
  • 1. Endogenous NDPK-B is also critical for KCa3.1 channel activity and the subsequent activation of CD4 T cells [7].
  • 1. NDPK-B directly binds and activates KCa3.1 by phosphorylating histidine 358 in the carboxyl terminus of KCa3 [7].
  • Inhibitors of KCa3.1 are in development to treat autoimmune diseases and transplant rejection, underscoring the importance in understanding how these channels are regulated [7].
  • Here, we report that the gene encoding K(Ca)3.1 (KCNN4) contains a functional repressor element 1-silencing transcription factor (REST or NRSF) binding site and is repressed by REST [8].

Chemical compound and disease context of KCNN4


Biological context of KCNN4


Anatomical context of KCNN4

  • Patch-clamp studies of swelling-activated potassium currents in the three cell lines revealed that all of them possess a potassium current with the biophysical and pharmacological fingerprints of the intermediate conductance Ca(2+)-dependent potassium channel (IK, also known as KCNN4) [16].
  • (4) Using apically permeabilised epithelia it was shown that 7,8-benzoquinoline activates an intermediate-conductance calcium-sensitive potassium channel (KCNN4) and a cAMP-sensitive potassium channel (KCNQ1/KCNE3) in the basolateral epithelial membranes [17].
  • Expression of intermediate-conductance, Ca2+-activated K+ channel (KCNN4) in H441 human distal airway epithelial cells [18].
  • In inside-out patches of red cell membranes, the open probability (Po) of the Gardos channel is markedly reduced when the temperature is raised from 27 to 37 degrees C. Net K+ efflux of intact red cells is also reduced by increasing temperature, as are the Po values of inside-out patches of Chinese hamster ovary cells expressing SK4 (but not SK3) [19].
  • Thus the envelope of evidence indicates that SK4 is the gene that codes for the Gardos channel in human red blood cells [19].

Associations of KCNN4 with chemical compounds

  • Basolateral G(K) was reduced by the K+ channel inhibitors clotrimazole and clofilium, indicating roles for KCNN4 and KCNQ1 in the H2O2-stimulated response [20].
  • 5 Isolated inside-out patches from Calu-3 cells revealed clotrimazole-sensitive channels with a conductance of 12 pS at positive potentials after activation with CBIQ and demonstrating inwardly rectifying properties, consistent with the known properties of KCNN4 [21].
  • Subsequent studies showed that 1-EBIO stimulates Na(+) transport in polarized monolayers without affecting intracellular Ca(2+) concentration ([Ca(2+)](i)), suggesting that the activity of KCNN4 might influence the rate of Na(+) absorption by contributing to G(K) [18].
  • 4-Chloro-benzo[F]isoquinoline (CBIQ) activates CFTR chloride channels and KCNN4 potassium channels in Calu-3 human airway epithelial cells [21].
  • The increase in G(Tot) was antagonized by Ba(2+), a nonselective K(+) channel blocker, and abolished by clotrimazole, a KCNN4 inhibitor, but unaffected by other selective K(+) channel blockers [18].

Regulatory relationships of KCNN4

  • Thus, Kv1.3 channels are essential for activation of quiescent cells, but signaling through the PKC pathway enhances expression of IKCa1 channels that are required for continued proliferation [14].
  • CONCLUSIONS: bFGF and VEGF upregulate expression of IKCa1 in human ECs [22].
  • We have addressed the issue of whether CpG will promote the production ofAMAs and whether new experimental agents that inhibit the lymphocyte potassium channels Kv1.3 and KCa3.1 can suppress CpG-mediated B cell activation and AMA production [23].

Other interactions of KCNN4

  • RT-PCR analysis showed expression of P2Y(1), P2Y(2), P2Y(11), P2X(1), P2X(4), and P2X(7) receptors, large-conductance (KCNMA1 and KCNMB1-4), and intermediate-conductance (KCNN4) Ca(2+)-activated K(+) channels [24].
  • We conclude that while KCNN4 contributes to Ca2+-activated anion secretion by Calu-3 cells, basal and cAMP-activated secretion are more critically dependent on other K+ channel types, possibly involving one or more class of KCNQ1-containing channel complexes [25].
  • 3 Apical membrane permeabilisation to allow recording of basolateral membrane conductance in the presence of a K+ gradient suggested that CBIQ activated the intermediate-conductance calcium-sensitive K(+)-channel (KCNN4) [21].
  • RT-PCR indicated expression of the Ca2+-activated K+ channel KCNN4, as well as the acid-sensitive, four transmembrane domain, two pore K+ channel, KCNK5 (hTASK-2) [26].
  • Heterologously expressed SK4, but not SK3, also shows this behavior [19].

Analytical, diagnostic and therapeutic context of KCNN4


  1. Human calcium-activated potassium channel gene KCNN4 maps to chromosome 19q13.2 in the region deleted in diamond-blackfan anemia. Ghanshani, S., Coleman, M., Gustavsson, P., Wu, A.C., Gargus, J.J., Gutman, G.A., Dahl, N., Mohrenweiser, H., Chandy, K.G. Genomics (1998) [Pubmed]
  2. 4-Chlorobenzo[F]isoquinoline (CBIQ), a novel activator of CFTR and DeltaF508 CFTR. Murthy, M., Pedemonte, N., MacVinish, L., Galietta, L., Cuthbert, A. Eur. J. Pharmacol. (2005) [Pubmed]
  3. Selective intermediate-/small-conductance calcium-activated potassium channel (KCNN4) blockers are potent and effective therapeutics in experimental brain oedema and traumatic brain injury caused by acute subdural haematoma. Mauler, F., Hinz, V., Horváth, E., Schuhmacher, J., Hofmann, H.A., Wirtz, S., Hahn, M.G., Urbahns, K. Eur. J. Neurosci. (2004) [Pubmed]
  4. Sickle cell disease: from membrane pathophysiology to novel therapies for prevention of erythrocyte dehydration. Brugnara, C. J. Pediatr. Hematol. Oncol. (2003) [Pubmed]
  5. Unexpected down-regulation of the hIK1 Ca2+-activated K+ channel by its opener 1-ethyl-2-benzimidazolinone in HaCaT keratinocytes. Inverse effects on cell growth and proliferation. Koegel, H., Kaesler, S., Burgstahler, R., Werner, S., Alzheimer, C. J. Biol. Chem. (2003) [Pubmed]
  6. Molecular physiology of cardiac potassium channels. Deal, K.K., England, S.K., Tamkun, M.M. Physiol. Rev. (1996) [Pubmed]
  7. Histidine Phosphorylation of the Potassium Channel KCa3.1 by Nucleoside Diphosphate Kinase B Is Required for Activation of KCa3.1 and CD4 T Cells. Srivastava, S., Li, Z., Ko, K., Choudhury, P., Albaqumi, M., Johnson, A.K., Yan, Y., Backer, J.M., Unutmaz, D., Coetzee, W.A., Skolnik, E.Y. Mol. Cell (2006) [Pubmed]
  8. Downregulated REST transcription factor is a switch enabling critical potassium channel expression and cell proliferation. Cheong, A., Bingham, A.J., Li, J., Kumar, B., Sukumar, P., Munsch, C., Buckley, N.J., Neylon, C.B., Porter, K.E., Beech, D.J., Wood, I.C. Mol. Cell (2005) [Pubmed]
  9. Role of Ca2+-activated K+ channels in human erythrocyte apoptosis. Lang, P.A., Kaiser, S., Myssina, S., Wieder, T., Lang, F., Huber, S.M. Am. J. Physiol., Cell Physiol. (2003) [Pubmed]
  10. Chronic angiotensin II stimulation in the heart produces an acquired long QT syndrome associated with IK1 potassium current downregulation. Domenighetti, A.A., Boixel, C., Cefai, D., Abriel, H., Pedrazzini, T. J. Mol. Cell. Cardiol. (2007) [Pubmed]
  11. Decreased potassium channel IK1 and its regulator neurotrophin-3 (NT-3) in inflamed human bowel. Arnold, S.J., Facer, P., Yiangou, Y., Chen, M.X., Plumpton, C., Tate, S.N., Bountra, C., Chan, C.L., Williams, N.S., Anand, P. Neuroreport (2003) [Pubmed]
  12. A human intermediate conductance calcium-activated potassium channel. Ishii, T.M., Silvia, C., Hirschberg, B., Bond, C.T., Adelman, J.P., Maylie, J. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  13. Phosphatidylinositol 3-phosphate indirectly activates KCa3.1 via 14 amino acids in the carboxy terminus of KCa3.1. Srivastava, S., Choudhury, P., Li, Z., Liu, G., Nadkarni, V., Ko, K., Coetzee, W.A., Skolnik, E.Y. Mol. Biol. Cell (2006) [Pubmed]
  14. Up-regulation of the IKCa1 potassium channel during T-cell activation. Molecular mechanism and functional consequences. Ghanshani, S., Wulff, H., Miller, M.J., Rohm, H., Neben, A., Gutman, G.A., Cahalan, M.D., Chandy, K.G. J. Biol. Chem. (2000) [Pubmed]
  15. Modulation of Ca2+-activated Cl- secretion by basolateral K+ channels in human normal and cystic fibrosis airway epithelia. Mall, M., Gonska, T., Thomas, J., Schreiber, R., Seydewitz, H.H., Kuehr, J., Brandis, M., Kunzelmann, K. Pediatr. Res. (2003) [Pubmed]
  16. Defective regulatory volume decrease in human cystic fibrosis tracheal cells because of altered regulation of intermediate conductance Ca2+-dependent potassium channels. Vázquez, E., Nobles, M., Valverde, M.A. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  17. Mechanisms of anion secretion in Calu-3 human airway epithelial cells by 7,8-benzoquinoline. Cuthbert, A.W., MacVinish, L.J. Br. J. Pharmacol. (2003) [Pubmed]
  18. Expression of intermediate-conductance, Ca2+-activated K+ channel (KCNN4) in H441 human distal airway epithelial cells. Wilson, S.M., Brown, S.G., McTavish, N., McNeill, R.P., Husband, E.M., Inglis, S.K., Olver, R.E., Clunes, M.T. Am. J. Physiol. Lung Cell Mol. Physiol. (2006) [Pubmed]
  19. The hSK4 (KCNN4) isoform is the Ca2+-activated K+ channel (Gardos channel) in human red blood cells. Hoffman, J.F., Joiner, W., Nehrke, K., Potapova, O., Foye, K., Wickrema, A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  20. Oxidant stress stimulates anion secretion from the human airway epithelial cell line Calu-3: implications for cystic fibrosis lung disease. Cowley, E.A., Linsdell, P. J. Physiol. (Lond.) (2002) [Pubmed]
  21. 4-Chloro-benzo[F]isoquinoline (CBIQ) activates CFTR chloride channels and KCNN4 potassium channels in Calu-3 human airway epithelial cells. Szkotak, A.J., Murthy, M., MacVinish, L.J., Duszyk, M., Cuthbert, A.W. Br. J. Pharmacol. (2004) [Pubmed]
  22. Selective blockade of the intermediate-conductance Ca2+-activated K+ channel suppresses proliferation of microvascular and macrovascular endothelial cells and angiogenesis in vivo. Grgic, I., Eichler, I., Heinau, P., Si, H., Brakemeier, S., Hoyer, J., Köhler, R. Arterioscler. Thromb. Vasc. Biol. (2005) [Pubmed]
  23. AMA production in primary biliary cirrhosis is promoted by the TLR9 ligand CpG and suppressed by potassium channel blockers. Moritoki, Y., Lian, Z.X., Wulff, H., Yang, G.X., Chuang, Y.H., Lan, R.Y., Ueno, Y., Ansari, A.A., Coppel, R.L., Mackay, I.R., Gershwin, M.E. Hepatology (2007) [Pubmed]
  24. Extracellular ATP induces oscillations of intracellular Ca2+ and membrane potential and promotes transcription of IL-6 in macrophages. Hanley, P.J., Musset, B., Renigunta, V., Limberg, S.H., Dalpke, A.H., Sus, R., Heeg, K.M., Preisig-Müller, R., Daut, J. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  25. Characterization of basolateral K+ channels underlying anion secretion in the human airway cell line Calu-3. Cowley, E.A., Linsdell, P. J. Physiol. (Lond.) (2002) [Pubmed]
  26. Characterization of vectorial chloride transport pathways in the human pancreatic duct adenocarcinoma cell line HPAF. Fong, P., Argent, B.E., Guggino, W.B., Gray, M.A. Am. J. Physiol., Cell Physiol. (2003) [Pubmed]
  27. Exposure to sodium butyrate leads to functional downregulation of calcium-activated potassium channels in human airway epithelial cells. Roy, J., Denovan-Wright, E.M., Linsdell, P., Cowley, E.A. Pflugers Arch. (2006) [Pubmed]
  28. Molecular localization of the inhibitory arachidonic acid binding site to the pore of hIK1. Hamilton, K.L., Syme, C.A., Devor, D.C. J. Biol. Chem. (2003) [Pubmed]
  29. Role of the NH2 terminus in the assembly and trafficking of the intermediate conductance Ca2+-activated K+ channel hIK1. Jones, H.M., Hamilton, K.L., Papworth, G.D., Syme, C.A., Watkins, S.C., Bradbury, N.A., Devor, D.C. J. Biol. Chem. (2004) [Pubmed]
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