Advertisement

Molecular and Cellular Biochemistry

, Volume 300, Issue 1–2, pp 9–17 | Cite as

Transcriptional regulation of intronic calcium-activated potassium channel SK2 promoters by nuclear factor-kappa B and glucocorticoids

  • Min-Jeong Kye
  • Joachim Spiess
  • Thomas Blank
Article

Abstract

Small-conductance Ca2+-activated K+ channels (SK) of the SK2 subtype are widely expressed in the central nervous system where they contribute to the control of neuronal excitability. Two SK2 isoforms, SK2-S and SK2-L, the latter representing an N-terminally extended protein of SK2-S, are expressed in similar patterns in the brain. However, our understanding of mechanisms by which the expression of SK2 is regulated is limited. We identified one functional glucocorticoid response element (GRE) at position −2248 bp and two functional nuclear factor-kappB (NF-kappaB) response elements at positions –1652 and –1586 bp in the SK2-S promoter. An increase in SK2-S promoter activity was observed in PC12 cells transiently transfected with a wild-type SK2-S promoter-luciferase reporter gene construct and treated with aldosterone or dexamethasone. The mineralocorticoid receptor (MR) antagonist spironolactone or the glucocorticoid receptor (GR) antagonist mifepristone fully inhibited aldosterone or dexamethasone activation of the SK2-S promoter, respectively. SK2-S promoter activity was also induced by the cell-permeable ceramide analog, N-acetylsphingosine (C2-ceramide). Antisense oligonucleotides directed to NF-kappaB p65 or p50 suppressed SK2-S transcription induced by C2-ceramide. Deletion studies showed that only the −1586 bp NF-kappaB binding site was necessary for maximum C2-ceramide response. Finally, we showed that activation of GRs but not of MRs repressed the NF-kappaB-mediated induction of SK2-S transcription. These findings suggest a possible transcriptional cross talk between GRs and NF-kappaB in the intronic promoter regulation of SK2-S channel gene transcription.

Keywords

corticosteroids cross-talk NF-kappaB promoter SK2 stress 

Abbreviations

SK

small-conductance calcium-activated potassium channel

GRE

glucocorticoid response element

AHP

afterhyperpolarization

GR

glucocorticoid receptor

MR

mineralocorticoid receptor

PCR

polymerase chain reaction

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Notes

Acknowledgments

This work was supported by the Max-Planck Society and␣NIH grant 2U54NSO39406-06. The authors are thankful to Saravanna Murthy for his critical comments on the manuscript.

References

  1. 1.
    De Kloet ER, Oitzl MS, Joels M (1999) Stress and cognition: are corticosteroids good or bad guys? Trends Neurosci 22: 422–426PubMedCrossRefGoogle Scholar
  2. 2.
    Kim JJ, Diamond DM (2002) The stressed hippocampus, synaptic plasticity and lost memories Nat Rev Neurosci 3: 453–462PubMedCrossRefGoogle Scholar
  3. 3.
    Smith MA, Makino S, Kvetnansky R, Post RM (1995) Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus J Neurosci 15: 1768–1777PubMedGoogle Scholar
  4. 4.
    Joels M, Velzing E, Nair S, Verkuyl JM, Karst H (2003) Acute stress increases calcium current amplitude in rat hippocampus: temporal changes in physiology and gene expression Eur J Neurosci 18: 1315–1324 PubMedCrossRefGoogle Scholar
  5. 5.
    Nijholt I, Farchi N, Kye M, Sklan EH, Shoham S, Verbeure B, Owen D, Hochner B, Spiess J, Soreq H, Blank T (2004) Stress-induced alternative splicing of acetylcholinesterase results in enhanced fear memory and long-term potentiation Mol Psychiatry 9: 174–183PubMedCrossRefGoogle Scholar
  6. 6.
    Blank T, Nijholt I, Spiess J (2004) Molecular determinants mediating effects of acute stress on hippocampus-dependent synaptic plasticity and learning Mol Neurobiol 29: 131–138PubMedCrossRefGoogle Scholar
  7. 7.
    McEwen BS, De Kloet ER, Rostene W (1986) Adrenal steroid receptors and actions in the nervous system Physiol Rev 66: 1121–1188PubMedGoogle Scholar
  8. 8.
    De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M (1998) Brain corticosteroid receptor balance in health and disease Endocr Rev 19: 269–301PubMedCrossRefGoogle Scholar
  9. 9.
    De Kloet ER, Oitzl MS, Joels M (1993) Functional implications of brain corticosteroid receptor diversity Cell Mol Neurobiol 13: 433–455 PubMedCrossRefGoogle Scholar
  10. 10.
    Van Steensel B, van Binnendijk EP, Hornsby CD, van der Voort HT, Krozowski ZS, De Kloet ER, van Driel R (1996) Partial colocalization of glucocorticoid and mineralocorticoid receptors in discrete compartments in nuclei of rat hippocampus neurons J Cell Sci 109: 787–792PubMedGoogle Scholar
  11. 11.
    Kye M, Nijholt I, Spiess J, Blank T (2003) Stress and corticosterone regulate SK2 gene expression in mouse hippocampus Soc Neurosci Abstr 29: 25217Google Scholar
  12. 12.
    Stocker M, Pedarzani P (2000) Differential distribution of three Ca(2+)-activated K(+) channel subunits, SK1, SK2, and SK3, in the adult rat central nervous system Mol Cell Neurosci 15: 476–493PubMedCrossRefGoogle Scholar
  13. 13.
    Sailer CA, Hu H, Kaufmann WA, Trieb M, Schwarzer C, Storm JF, Knaus HG (2002) Regional differences in distribution and functional expression of small-conductance Ca2+-activated K+ channels in rat brain J Neurosci 22: 9698–9707PubMedGoogle Scholar
  14. 14.
    Villalobos C, Shakkottai VG, Chandy KG, Michelhaugh SK, Andrade R (2004) SKCa channels mediate the medium but not the slow calcium-activated afterhyperpolarization in cortical neurons J Neurosci 24: 3537–3542PubMedCrossRefGoogle Scholar
  15. 15.
    Bond CT, Herson PS, Strassmaier T, Hammond R, Stackman R, Maylie J, Adelman JP (2004) Small conductance Ca2+-activated K+ channel knock-out mice reveal the identity of calcium-dependent afterhyperpolarization currents J Neurosci 24: 5301–5306PubMedCrossRefGoogle Scholar
  16. 16.
    Gu N, Vervaeke K, Hu H, Storm JF (2005) Kv7/KCNQ/M and HCN/h, but not KCa2/SK channels, contribute to the somatic medium after-hyperpolarization (mAHP) and excitability control in CA1 hippocampal pyramidal cells J Physiol 566: 689–715PubMedCrossRefGoogle Scholar
  17. 17.
    Stocker M, Krause M, Pedarzani P (1999) An apamin-sensitive Ca2+-activated K+ current in hippocampal pyramidal neurons Proc Natl Acad Sci USA 96: 4662–4667PubMedCrossRefGoogle Scholar
  18. 18.
    Stackman RW, Hammond RS, Linardatos E, Gerlach A, Maylie J, Adelman JP, Tzounopoulos T (2002) Small conductance Ca2+-activated K+ channels modulate synaptic plasticity and memory encoding J Neurosci 22: 10163–10171PubMedGoogle Scholar
  19. 19.
    Strassmaier T, Bond CT, Sailer CA, Knaus HG, Maylie J, Adelman JP (2005) A Novel Isoform of SK2 Assembles with Other SK Subunits in Mouse Brain J Biol Chem 280: 21231–21236PubMedCrossRefGoogle Scholar
  20. 20.
    Baldwin AS Jr (1996) The NF-kappa B and I kappa-B proteins: new discoveries and insights Annu Rev Immunol 14: 649–683PubMedCrossRefGoogle Scholar
  21. 21.
    Blank T, Nijholt I, Kye MJ, Radulovic J, Spiess J (2003) Small-conductance, Ca2+-activated K+ channel SK3 generates age-related memory and LTP deficits Nat Neurosci 6: 911–912PubMedCrossRefGoogle Scholar
  22. 22.
    Lin YZ, Yao SY, Veach RA, Torgerson TR, Hawiger J (1995) Inhibition of nuclear translocation of transcription factor NF-κB by a synthetic peptide containing a cell membrane-permeable motif and nuclear localization sequence J Biol Chem 270: 14255–14258PubMedCrossRefGoogle Scholar
  23. 23.
    Darios F, Corti O, Lucking CB, Hampe C, Muriel MP, Abbas N, Gu WJ, Hirsch EC, Rooney T, Ruberg M, Brice A (2003) Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death Hum Mol Genet 12: 517–526PubMedCrossRefGoogle Scholar
  24. 24.
    France-Lanord V, Brugg B, Michel PP, Agid Y, Ruberg M (1997) Mitochondrial free radical signal in ceramide-dependent apoptosis: a putative mechanism for neuronal death in Parkinson’s disease J Neurochem 69; 1612–1621PubMedCrossRefGoogle Scholar
  25. 25.
    De Kloet ER (1995) Steroids, stability and stress. Front Neuroendocrinol 16: 416–425PubMedCrossRefGoogle Scholar
  26. 26.
    De Kloet ER, Rots NY, Cools AR (1996) Brain-corticosteroid hormone dialogue: slow and persistent Cell Mol Neurobiol 16: 345–356PubMedCrossRefGoogle Scholar
  27. 27.
    Bierhaus A, Wolf J, Andrassy M, Rohleder N, Humpert PM, Petrov D, Ferstl R, von Eynatten M, Wendt T, Rudofsky G, Joswig M, Morcos M, Schwaninger M, McEwen B, Kirschbaum C, Nawroth PP (2003) A mechanism converting psychosocial stress into mononuclear cell activation Proc Natl Acad Sci USA 100: 1920–1925PubMedCrossRefGoogle Scholar
  28. 28.
    Mattson MP, Culmsee C, Yu ZF, Camandola S (2000) Roles of nuclear factor κB in neuronal survival, plasticity. J Neurochem 74: 443–465PubMedCrossRefGoogle Scholar
  29. 29.
    Carroll JE, Howard EF, Hess DC, Wakade CG, Chen Q, Cheng C (1998) Nuclear factor-kappa B activation during cerebral reperfusion: effect of attenuation with N-acetylcysteine treatment. Brain Res Mol Brain Res 56: 186–191PubMedCrossRefGoogle Scholar
  30. 30.
    Clemens JA, Stephenson DT, Smalstig EB, Dixon EP, Little SP (1997) Global ischemia activates nuclear factor-kappa B in forebrain neurons of rats. Stroke 28: 1073–1080PubMedGoogle Scholar
  31. 31.
    Culmsee C, Siewe J, Junker V, Retiounskaia M, Schwarz S, Camandola S, El-Metainy S, Behnke H, Mattson MP, Krieglstein J (2003) Reciprocal inhibition of p53 and nuclear factor-kappaB transcriptional activities determines cell survival or death in neurons. J Neurosci 23: 8586–8595PubMedGoogle Scholar
  32. 32.
    Kaltschmidt C, Kaltschmidt B, Neumann H, Wekerle H, Baeuerle PA (1994) Constitutive NF-kappaB activity in neurons. Mol Cell Biol 14: 3981–3992PubMedGoogle Scholar
  33. 33.
    Bakalkin GY, Yakovleva T, Terenius L (1993) NF-kappaB-like factors in the murine brain. Developmentally-regulated and tissue-specific expression. Mol Brain Res 20: 137–146PubMedCrossRefGoogle Scholar
  34. 34.
    Guerrini L, Blasi F, Denis-Donini S (1995) Synaptic activation of NF-kappaB by glutamate in cerebellar granule neurons in vitro. Proc Natl Acad Sci USA 92: 9077–9081PubMedCrossRefGoogle Scholar
  35. 35.
    Kaltschmidt C, Kaltschmidt B, Baeuerle PA (1995) Stimulation of ionotropic glutamate receptors activates transcription factor NF-kappa B in primary neurons. Proc Natl Acad Sci USA 92: 9618–9622PubMedCrossRefGoogle Scholar
  36. 36.
    Meberg PJ, Kinney WR, Valcourt EG, Routtenberg A (1996) Gene expression of the transcription factor NF-kappaB in hippocampus: regulation by synaptic activity. Mol Brain Res 38: 179–190PubMedCrossRefGoogle Scholar
  37. 37.
    Unlap T, Jope RS (1995) Inhibition of NF-kappaB DNA binding activity by glucocorticoids in rat brain. Neurosci Lett 198: 41–44PubMedCrossRefGoogle Scholar
  38. 38.
    Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M (1995) Immunosuppression by glucocorticoids: Inhibition of NF- kappaB activity through induction of I kappa B synthesis. Science 270: 286–290PubMedCrossRefGoogle Scholar
  39. 39.
    Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS, Jr (1995) Role of transcriptional activation of I kappaB in mediation of immunosuppression by glucocorticoids. Science 270: 283–286PubMedCrossRefGoogle Scholar
  40. 40.
    Van de Stolpe A, Caldenhoven E, Raaijmakers JA, van der Saag PT, Koenderman L (1993) Glucocorticoid-mediated repression of intercellular adhesion molecule-1 expression in human monocytic and bronchial epithelial cell lines. Am J Respir Cell Mol Biol 8: 340–347PubMedGoogle Scholar
  41. 41.
    Wissink S, van Heerde EC, van der Burg B, van der Saag PT (1998) A dual mechanism mediates repression of NF-kappaB activity by glucocorticoids. Mol Endocrinol 12: 355–363PubMedCrossRefGoogle Scholar
  42. 42.
    Liden J, Delaunay F, Rafter I, Gustafsson J, Okret S (1997) A new function for the C-terminal zinc finger of the glucocorticoid receptor repression of RelA transactivation. J Biol Chem 272: 21467–21472PubMedCrossRefGoogle Scholar
  43. 43.
    Wissink S, van Heerde EC, Schmitz ML, Kalkhoven E, van der Burg B, Baeuerle PA, van der Saag PT (1997) Distinct domains of the RelA NF-kappaB subunit are required for negative cross-talk and direct interaction with the glucocorticoid receptor. J Biol Chem 272: 22278–22284PubMedCrossRefGoogle Scholar
  44. 44.
    Meijer OC, Williamson A, Dallman MF, Pearce D (2000) Transcriptional repression of the 5-HT1A receptor promoter by corticosterone via mineralocorticoid receptors depends on the cellular context. J Neuroendocrinol 12: 245–254PubMedCrossRefGoogle Scholar
  45. 45.
    Wissink S, Meijer O, Pearce D, van Der Burg B, van Der Saag PT (2000) Regulation of the rat serotonin-1A receptor gene by corticosteroids. J Biol Chem 275: 1321–1326PubMedCrossRefGoogle Scholar
  46. 46.
    Rong Y, Baudry M (1996) Seizure activity results in a rapid induction of nuclear factor-kappa B in adult but not juvenile rat limbic structures. J Neurochem 67: 662–668PubMedCrossRefGoogle Scholar
  47. 47.
    Matsuoka Y, Kitamura Y, Okazaki M, Terai K, Taniguchi T (1999) Kainic acid-induced activation of nuclear factor-kappaB in rat hippocampus. Exp Brain Res 124: 215–222PubMedCrossRefGoogle Scholar
  48. 48.
    Goodman Y, Mattson MP (1996) Ceramide protects hippocampal neurons against excitotoxic and oxidative insults, and amyloid ß-peptide toxicity. J Neurochem 66: 869–872PubMedCrossRefGoogle Scholar
  49. 49.
    Lee AL, Dumas TC, Tarapore PE, Webster BR, Ho DY, Kaufer D, Sapolsky RM (2003) Potassium channel gene therapy can prevent neuron death resulting from necrotic and apoptotic insults. J Neurochem 86: 1079–1088PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Department of Molecular NeuroendocrinologyMax Planck Institute for Experimental MedicineGoettingenGermany
  2. 2.Specialized Neuroscience Research Program II, JABSOMUniversity of HawaiiHonoluluHawaii

Personalised recommendations