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

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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.

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Abbreviations

SK:

small-conductance calcium-activated potassium channel

GRE:

glucocorticoid response element

AHP:

afterhyperpolarization

GR:

glucocorticoid receptor

MR:

mineralocorticoid receptor

PCR:

polymerase chain reaction

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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.

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Author notes

  1. Min-Jeong Kye

    Present address: University of California, Neuroscience Research Institute, BLDG. 571, Santa Barbara, CA, USA

Authors and Affiliations

  1. Department of Molecular Neuroendocrinology, Max Planck Institute for Experimental Medicine, Goettingen, Germany

    Min-Jeong Kye, Joachim Spiess & Thomas Blank

  2. Specialized Neuroscience Research Program II, JABSOM, University of Hawaii, Honolulu, HI, Hawaii

    Joachim Spiess & Thomas Blank

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  1. Min-Jeong Kye
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Correspondence to Thomas Blank.

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Kye, MJ., Spiess, J. & Blank, T. Transcriptional regulation of intronic calcium-activated potassium channel SK2 promoters by nuclear factor-kappa B and glucocorticoids. Mol Cell Biochem 300, 9–17 (2007). https://doi.org/10.1007/s11010-006-9320-6

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