| HERG K channel conductance promotes H2O2-induced apoptosis in HEK293 cells: cellular mechanisms. | |
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MedLine Citation:
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PMID: 15107589 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The human ether-a-go-go-related gene (HERG) encodes a delayed rectifier K(+) channel, which is expressed in a variety of tissues and cells. Besides its well-recognized function in cellular electrophysiology, HERG channels have also been implicated in neuronal differentiation and cell cycle regulation. We have recently found that HERG regulates apoptosis. To elucidate the signaling pathways, we performed studies in HEK293 cells stably expressing HERG channels. ELISA was used to quantify DNA fragmentation, a biochemical hallmark of apoptosis. In HERG-transfected HEK cells, the degree of DNA fragmentation was found consistently higher (approximately 4-times) than in non-transfected cells. Correspondingly, remarkable activation of caspase 3, caspase 9 and cleavage of PARP were seen in HERG-expressing cells, which were otherwise minimal in non-transfected cells. Exposure of cells to H(2)O(2) (10 hrs) at concentrations up to 1 mM, which is known to induce apoptosis in a variety of cells, caused minimal DNA fragmentation in non-transfected cells. HERG expression facilitates DNA fragmentation induced by H(2)O(2) at a concentration-dependent fashion, starting at 200 microM and reaching maximum at 1 mM. Selective HERG channel inhibitors, dofetilide or E-4031 (5 microM) prevented DNA fragmentation. Inhibition of p38 by SB-203580 alleviated DNA-F and PD-98059, which inhibited activation of ERKs, nearly abolished DNA-F. Immunoblotting analysis demonstrated that p38, SAPKs and ERKs MAP kinases were all substantially activated (>10-fold higher) in HERG-expressing cells vs. non-transfected cells. Akt activity was approximately 4-fold lower in HERG cells vs. non-transfected cells in the absence of H(2)O(2) and was slightly increased (approximately 2-fold) after H(2)O(2) exposure. We conclude that HERG channels facilitate cellular DNA fragmentation in HEK cells via concomitant activation of MAP kinases and inactivation of Akt. |
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Authors:
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Hong Han; Jingxiong Wang; Yiqiang Zhang; Hong Long; Huizhen Wang; Donghui Xu; Zhiguo Wang |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology Volume: 14 ISSN: 1015-8987 ISO Abbreviation: Cell. Physiol. Biochem. Publication Date: 2004 |
Date Detail:
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Created Date: 2004-04-26 Completed Date: 2005-04-14 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 9113221 Medline TA: Cell Physiol Biochem Country: Switzerland |
Other Details:
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Languages: eng Pagination: 121-34 Citation Subset: IM |
Copyright Information:
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Copyright 2004 S. Karger AG, Basel |
Affiliation:
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Research Center, Montreal Heart Institute, Quebec, Canada. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Anti-Arrhythmia Agents Caspase 3 Caspase 9 Caspases / metabolism Cell Line DNA Fragmentation / drug effects* Enzyme Inhibitors / pharmacology Ether-A-Go-Go Potassium Channels Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors, metabolism Flavonoids / metabolism Humans Hydrogen Peroxide / pharmacology* Imidazoles / pharmacology Piperidines / pharmacology Poly(ADP-ribose) Polymerases / metabolism Potassium Channels, Voltage-Gated / genetics, metabolism* Pyridines / pharmacology Signal Transduction / drug effects p38 Mitogen-Activated Protein Kinases / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Anti-Arrhythmia Agents; 0/ERG1 potassium channel; 0/Enzyme Inhibitors; 0/Ether-A-Go-Go Potassium Channels; 0/Flavonoids; 0/Imidazoles; 0/PD 98059; 0/Piperidines; 0/Potassium Channels, Voltage-Gated; 0/Pyridines; 0/SB 203580; 113558-89-7/E 4031; 7722-84-1/Hydrogen Peroxide; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/CASP9 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 9; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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