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Nanoelectropulse-Induced Phosphatidylserine Translocation

P. Thomas Vernier ^* , Yinghua Sun , Laura Marcu ^*  ¶, Cheryl M. Craft ^|| and Martin A. Gundersen ^*

^* Department of Electrical Engineering-Electrophysics, School of Engineering, MOSIS, Information Sciences Institute, School of Engineering, Department of Materials Science, School of Engineering, Department of Biomedical Engineering, School of Engineering, University of Southern California, Los Angeles, California; ^¶ Biophotonics Research and Technology Development Laboratory, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California; and ^|| Mary D. Allen Laboratory for Vision Research, Doheny Eye Institute, and Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California

Correspondence: Address reprint requests to P. Thomas Vernier, MOSIS, USC-ISI, 4676 Admiralty Way, Marina del Rey, CA 90292. Tel.: 310-448-8752; Fax: 310-823-5624; E-mail: vernier{at}mosis.org.

Nanosecond, megavolt-per-meter, pulsed electric fields induce phosphatidylserine (PS) externalization, intracellular calcium redistribution, and apoptosis in Jurkat T-lymphoblasts, without causing immediately apparent physical damage to the cells. Intracellular calcium mobilization occurs within milliseconds of pulse exposure, and membrane phospholipid translocation is observed within minutes. Pulsed cells maintain cytoplasmic membrane integrity, blocking propidium iodide and Trypan blue. Indicators of apoptosis—caspase activation and loss of mitochondrial membrane potential—appear in nanoelectropulsed cells at later times. Although a theoretical framework has been established, specific mechanisms through which external nanosecond pulsed electric fields trigger intracellular responses in actively growing cells have not yet been experimentally characterized. This report focuses on the membrane phospholipid rearrangement that appears after ultrashort pulse exposure. We present evidence that the minimum field strength required for PS externalization in actively metabolizing Jurkat cells with 7-ns pulses produces transmembrane potentials associated with increased membrane conductance when pulse widths are microseconds rather than nanoseconds. We also show that nanoelectropulse trains delivered at repetition rates from 2 to 2000 Hz have similar effects, that nanoelectropulse-induced PS externalization does not require calcium in the external medium, and that the pulse regimens used in these experiments do not cause significant intra- or extracellular Joule heating.

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