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(Received for publication, June 26, 1997, and in revised form, September 4, 1997)
From the Laboratory of Signal Transduction, NIEHS, National
Institutes of Health, Research Triangle Park,
North Carolina 27709
Little is known about the mechanisms of
suppression of apoptosis. We have addressed the novel possibility that
the level of intracellular K+ regulates the apoptotic
process by controlling the activity of death enzymes. We show that
K+, at normal intracellular levels, inhibits both apoptotic
DNA fragmentation and caspase-3(CPP32)-like protease activation,
suggesting that intracellular K+ loss must occur early
during apoptosis. Direct measurement of K+ by inductively
coupled plasma/mass spectrometry and flow cytometry indicates a major
decrease in intracellular K+ concentration in the apoptotic
cell. Flow cytometric analysis revealed that caspase and nuclease
activity were restricted to the subpopulation of cells with reduced
K+. Disruption of the natural K+
electrochemical gradient suppressed the activity of both caspase and
nuclease independent of the mode of activation of the apoptotic inducing agent, demonstrating that a decrease in intracellular K+ concentration is a necessary, early event in programmed
cell death.
Volume 272, Number 48,
Issue of November 28, 1997
pp. 30567-30576
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
Intracellular K+ Suppresses the Activation of
Apoptosis in Lymphocytes
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D. G. Perregaux and C. A. Gabel Human monocyte stimulus-coupled IL-1beta posttranslational processing: modulation via monovalent cations Am J Physiol Cell Physiol, December 1, 1998; 275(6): C1538 - C1547. [Abstract] [Full Text] [PDF]
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 D. J. Walker, C. R. Black, and A. J. Miller The Role of Cytosolic Potassium and pH in the Growth of Barley Roots Plant Physiology, November 1, 1998; 118(3): 957 - 964. [Abstract] [Full Text]
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B. Dallaporta, T. Hirsch, S. A. Susin, N. Zamzami, N. Larochette, C. Brenner, I. Marzo, and G. Kroemer Potassium Leakage During the Apoptotic Degradation Phase J. Immunol., June 1, 1998; 160(11): 5605 - 5615. [Abstract] [Full Text] [PDF]
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R. Nadimpalli, N. Yalpani, G. S. Johal, and C. R. Simmons Prohibitins, Stomatins, and Plant Disease Response Genes Compose a Protein Superfamily That Controls Cell Proliferation, Ion Channel Regulation, and Death J. Biol. Chem., September 15, 2000; 275(38): 29579 - 29586. [Abstract] [Full Text] [PDF]
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H. H. Nietsch, M. W. Roe, J. F. Fiekers, A. L. Moore, and S. D. Lidofsky Activation of Potassium and Chloride Channels by Tumor Necrosis Factor alpha . ROLE IN LIVER CELL DEATH J. Biol. Chem., June 30, 2000; 275(27): 20556 - 20561. [Abstract] [Full Text] [PDF]
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A. B. Scoltock, C. D. Bortner, G. St. J. Bird, J. W. Putney Jr., and J. A. Cidlowski A Selective Requirement for Elevated Calcium in DNA Degradation, but Not Early Events in Anti-Fas-induced Apoptosis J. Biol. Chem., September 22, 2000; 275(39): 30586 - 30596. [Abstract] [Full Text] [PDF]
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C. D. Bortner, M. Gomez-Angelats, and J. A. Cidlowski Plasma Membrane Depolarization without Repolarization Is an Early Molecular Event in Anti-Fas-induced Apoptosis J. Biol. Chem., February 2, 2001; 276(6): 4304 - 4314. [Abstract] [Full Text] [PDF]
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C. C. Q. Vu, C. D. Bortner, and J. A. Cidlowski Differential Involvement of Initiator Caspases in Apoptotic Volume Decrease and Potassium Efflux during Fas- and UV-induced Cell Death J. Biol. Chem., September 28, 2001; 276(40): 37602 - 37611. [Abstract] [Full Text] [PDF]
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M. Gomez-Angelats, C. D. Bortner, and J. A. Cidlowski Protein Kinase C (PKC) Inhibits Fas Receptor-induced Apoptosis through Modulation of the Loss of K+ and Cell Shrinkage. A ROLE FOR PKC UPSTREAM OF CASPASES J. Biol. Chem., June 23, 2000; 275(26): 19609 - 19619. [Abstract] [Full Text] [PDF]
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E. Maeno, Y. Ishizaki, T. Kanaseki, A. Hazama, and Y. Okada From the Cover: Normotonic cell shrinkage because of disordered volume regulation is an early prerequisite to apoptosis PNAS, August 15, 2000; 97(17): 9487 - 9492. [Abstract] [Full Text] [PDF]
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J. R. Trimarchi, L. Liu, P. J. S. Smith, and D. L. Keefe Apoptosis recruits two-pore domain potassium channels used for homeostatic volume regulation Am J Physiol Cell Physiol, March 1, 2002; 282(3): C588 - C594. [Abstract] [Full Text] [PDF]
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