Document Detail

Hydrogen peroxide removes TRPM4 current desensitization conferring increased vulnerability to necrotic cell death.
MedLine Citation:
PMID:  20884614     Owner:  NLM     Status:  MEDLINE    
Necrosis is associated with an increase in plasma membrane permeability, cell swelling, and loss of membrane integrity with subsequent release of cytoplasmic constituents. Severe redox imbalance by overproduction of reactive oxygen species is one of the main causes of necrosis. Here we demonstrate that H(2)O(2) induces a sustained activity of TRPM4, a Ca(2+)-activated, Ca(2+)-impermeant nonselective cation channel resulting in an increased vulnerability to cell death. In HEK 293 cells overexpressing TRPM4, H(2)O(2) was found to eliminate in a dose-dependent manner TRPM4 desensitization. Site-directed mutagenesis experiments revealed that the Cys(1093) residue is crucial for the H(2)O(2)-mediated loss of desensitization. In HeLa cells, which endogenously express TRPM4, H(2)O(2) elicited necrosis as well as apoptosis. H(2)O(2)-mediated necrosis but not apoptosis was abolished by replacement of external Na(+) ions with sucrose or the non-permeant cation N-methyl-d-glucamine and by knocking down TRPM4 with a shRNA directed against TRPM4. Conversely, transient overexpression of TRPM4 in HeLa cells in which TRPM4 was previously silenced re-established vulnerability to H(2)O(2)-induced necrotic cell death. In addition, HeLa cells exposed to H(2)O(2) displayed an irreversible loss of membrane potential, which was prevented by TRPM4 knockdown.
Felipe Simon; Elías Leiva-Salcedo; Ricardo Armisén; Ana Riveros; Oscar Cerda; Diego Varela; Ana Luisa Eguiguren; Pablo Olivero; Andrés Stutzin
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-09-30
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-24     Completed Date:  2010-12-30     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  37150-8     Citation Subset:  IM    
Centro de Estudios Moleculares de la Célula and Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Av Independencia 1027, Independencia 838-0543, Santiago, Chile.
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MeSH Terms
Amino Acid Motifs
Cell Membrane / chemistry,  metabolism
HEK293 Cells
HeLa Cells
Hydrogen Peroxide / metabolism*
Membrane Potentials
Necrosis / genetics,  metabolism*
TRPM Cation Channels / chemistry,  genetics,  metabolism*
Reg. No./Substance:
0/TRPM Cation Channels; 0/TRPM4 protein, human; 7722-84-1/Hydrogen Peroxide

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