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Am J Physiol Cell Physiol 284: C1006-C1020, 2003. First published December 11, 2002; doi:10.1152/ajpcell.00258.2002
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Vol. 284, Issue 4, C1006-C1020, April 2003

Blockade of maitotoxin-induced endothelial cell lysis by glycine and L-alanine

Mark Estacion, Justin S. Weinberg, William G. Sinkins, and William P. Schilling

Rammelkamp Center for Education and Research, MetroHealth Medical Center and Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44109

The maitotoxin (MTX)-induced cell death cascade in bovine aortic endothelial cells (BAECs) is a model for oncotic/necrotic cell death. The cascade is initiated by an increase in cytosolic free Ca2+ concentration ([Ca2+]i), which is followed by the biphasic uptake of vital dyes. The initial phase of dye entry reflects activation of large pores and correlates with surface membrane bleb formation; the second phase reflects cell lysis. In the present study, the effect of the cytoprotective amino acid glycine was examined. Glycine had no effect on MTX-induced change in [Ca2+]i or on the first phase of vital dye uptake but produced a concentration-dependent (EC50 ~1 mM) inhibition of the second phase of dye uptake. No cytoprotective effect was observed with L-valine, L-proline, or D-alanine, whereas L-alanine was equieffective to glycine. Furthermore, glycine had no effect on MTX-induced bleb formation. To test the hypothesis that glycine specifically blocks formation of a lytic "pore," the loss of fluorescence from BAECs transiently expressing GFP and concatemers of GFP ranging in size from 27 to 162 kDa was examined using time-lapse videomicroscopy. MTX-induced loss of GFP was rapid, correlated with the second phase of dye uptake, and was relatively independent of molecular size. The MTX-induced loss of GFP from BAECs was completely blocked by glycine. The data suggest that the second "lytic" phase of MTX-induced endothelial cell death reflects formation of a novel permeability pathway that allows macromolecules such as GFP or LDH to escape, yet can be prevented by the cytoprotective agents glycine and L-alanine.

necrosis; vital dyes; membrane blebs; time-lapse videomicroscopy; fura 2


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