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Molecular Pharmacology

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Research ArticleArticle

Barbiturates Directly Inhibit the Calmodulin/Calcineurin Complex: a Novel Mechanism of Inhibition of Nuclear Factor of Activated T Cells

Matjaz Humar, Soeren E. Pischke, Torsten Loop, Alexander Hoetzel, Rene Schmidt, Christoph Klaas, Heike L. Pahl, Klaus K. Geiger and Benedikt H. J. Pannen
Molecular Pharmacology February 2004, 65 (2) 350-361; DOI: https://doi.org/10.1124/mol.65.2.350
Matjaz Humar
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Soeren E. Pischke
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Torsten Loop
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Alexander Hoetzel
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Rene Schmidt
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Christoph Klaas
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Heike L. Pahl
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Klaus K. Geiger
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Benedikt H. J. Pannen
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Abstract

Barbiturates are frequently used for the treatment of intracranial hypertension after brain injury but their application is associated with a profound increase in the infection rate. The mechanism of barbiturate-induced failure of protective immunity is still unknown. We provide evidence that nuclear factor of activated T cells (NFAT), an essential transcription factor in T cell activation, is a target of barbiturate-mediated immunosuppression in human T lymphocytes. Treatment of primary CD3+ lymphocytes with barbiturates inhibited the PMA and ionomycin induced increase in DNA binding of NFAT, whereas the activity of other transcription factors, such as Oct-1, SP-1, or the cAMP response element-binding protein, remained unaffected. Moreover, barbiturates suppressed the expression of a luciferase reporter gene under control of NFAT (stably transfected Jurkat T cells), and of the cytokine genes interleukin-2 and interferon-γ that contain functional binding motifs for NFAT within their regulatory promotor domains (human peripheral blood CD3+ lymphocytes). Neither GABA receptor-initiated signaling nor direct interactions of barbiturates with nuclear proteins affected the activity of NFAT. In contrast, barbiturates suppressed the calcineurin-dependent dephosphorylation of NFAT in intact T cells and also inhibited the enzymatic activity of calcineurin in a cell-free system, excluding upstream regulation. Thus, our results demonstrate a novel mechanism of direct inhibition of the calcineurin/calmodulin complex that may explain some of the known immunosuppressive effects associated with barbiturate treatment.

  • Received May 12, 2003.
  • Accepted October 17, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 65 (2)
Molecular Pharmacology
Vol. 65, Issue 2
1 Feb 2004
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Research ArticleArticle

Barbiturates Directly Inhibit the Calmodulin/Calcineurin Complex: a Novel Mechanism of Inhibition of Nuclear Factor of Activated T Cells

Matjaz Humar, Soeren E. Pischke, Torsten Loop, Alexander Hoetzel, Rene Schmidt, Christoph Klaas, Heike L. Pahl, Klaus K. Geiger and Benedikt H. J. Pannen
Molecular Pharmacology February 1, 2004, 65 (2) 350-361; DOI: https://doi.org/10.1124/mol.65.2.350

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Research ArticleArticle

Barbiturates Directly Inhibit the Calmodulin/Calcineurin Complex: a Novel Mechanism of Inhibition of Nuclear Factor of Activated T Cells

Matjaz Humar, Soeren E. Pischke, Torsten Loop, Alexander Hoetzel, Rene Schmidt, Christoph Klaas, Heike L. Pahl, Klaus K. Geiger and Benedikt H. J. Pannen
Molecular Pharmacology February 1, 2004, 65 (2) 350-361; DOI: https://doi.org/10.1124/mol.65.2.350
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