Attenuation of apoptosis in enterocytes by blockade of potassium channels

Anatoly Grishin, Henri Ford, Jin Wang, Hui Li, Vicenta Salvador-Recatala, Edwin S. Levitan, Elena Zaks-Makhina

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Apoptosis plays an important role in maintaining the balance between proliferation and cell loss in the intestinal epithelium. Apoptosis rates may increase in intestinal pathologies such as inflammatory bowel disease and necrotizing enterocolitis, suggesting pharmacological prevention of apoptosis as a therapy for these conditions. Here, we explore the feasibility of this approach using the rat epithelial cell line IEC-6 as a model. On the basis of the known role of K+ efflux in apoptosis in various cell types, we hypothesized that K+ efflux is essential for apoptosis in enterocytes and that pharmacological blockade of this efflux would inhibit apoptosis. By probing intracellular [K+] with the K+-sensitive fluorescent dye and measuring the efflux of 86Rb+, we found that apoptosis-inducing treatment with the proteasome inhibitor MG-132 leads to a twofold increase in K+ efflux from IEC-6 cells. Blockade of K+ efflux with tetraethylammonium, 4-aminopyridine, stromatoxin, chromanol 293B, and the recently described K+ channel inhibitor 48F10 prevents DNA fragmentation, caspase activation, release of cytochrome c from mitochondria, and loss of mitochondrial membrane potential. Thus K+ efflux occurs early in the apoptotic program and is required for the execution of later events. Apoptotic K+ efflux critically depends on activation of p38 MAPK. These results demonstrate for the first time the requirement of K+ channel-mediated K+ efflux for progression of apoptosis in enterocytes and suggest the use of K+ channel blockers to prevent apoptotic cell loss occurring in intestinal pathologies.

Original languageEnglish (US)
Pages (from-to)G815-G821
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume289
Issue number5 52-5
DOIs
StatePublished - Nov 1 2005
Externally publishedYes

Keywords

  • Apoptotic K efflux
  • IEC-6 cells
  • Intestinal pathologies
  • p38 mitogen-activated protein kinase

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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