Document Detail

Barbiturates directly inhibit the calmodulin/calcineurin complex: a novel mechanism of inhibition of nuclear factor of activated T cells.
MedLine Citation:
PMID:  14742677     Owner:  NLM     Status:  MEDLINE    
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-gamma 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.
Matjaz Humar; Soeren E Pischke; Torsten Loop; Alexander Hoetzel; Rene Schmidt; Christoph Klaas; Heike L Pahl; Klaus K Geiger; Benedikt H J Pannen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Molecular pharmacology     Volume:  65     ISSN:  0026-895X     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2004 Feb 
Date Detail:
Created Date:  2004-01-26     Completed Date:  2004-03-12     Revised Date:  2014-07-11    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  350-61     Citation Subset:  IM    
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MeSH Terms
Barbiturates / pharmacology*
Calcineurin / antagonists & inhibitors*,  metabolism
Calmodulin / antagonists & inhibitors*,  metabolism
Cytokines / genetics,  metabolism
DNA-Binding Proteins / antagonists & inhibitors*,  metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology*
Jurkat Cells
Lymphocytes / drug effects,  metabolism
NFATC Transcription Factors
Nuclear Proteins*
Transcription Factors / antagonists & inhibitors*,  metabolism
Reg. No./Substance:
0/Barbiturates; 0/Calmodulin; 0/Cytokines; 0/DNA-Binding Proteins; 0/Enzyme Inhibitors; 0/NFATC Transcription Factors; 0/Nuclear Proteins; 0/Transcription Factors; EC

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