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Abstract
Products of ras genes are putative elements of growth factor signal transduction. However, the mechanism of action of these proteins in normal and malignant growth is as yet obscure. To test for functional consequences of ras oncogene expression, electrophysiological experiments were performed on NIH-3T3 fibroblasts transfected with a transforming Ha-ras MMTV-LTR construct expressing the oncogene on treatment with dexamethasone (+ras). Transfected cells in the absence of dexamethasone (-ras) and nontransfected cells in the presence of dexamethasone (oras) served as controls. In -ras and oras, bradykinin induces a single, transient hyperpolarization. In +ras, bradykinin elicits oscillations of cell membrane potential throughout the presence of the hormone by activation of calcium-sensitive K+ channels. The oscillations of cell membrane potential are abolished in the absence of extracellular calcium. As evident from fura 2 fluorescence, bradykinin leads to a transient increase of intracellular calcium both in the presence and absence of extracellular calcium. Oscillations of intracellular calcium could be observed in +ras cells, if bradykinin was applied at reduced extracellular sodium concentration possibly to impair calcium extrusion via the sodium/calcium exchange. Bradykinin induces oscillations of cell membrane potential similarly in -ras cells loaded with GTP[S], a nonhydrolyzable analogue of GTP. Thus, the altered response of ras oncogene expressing cells to bradykinin relates to the GTP binding property of the ras protein. It is concluded that in cells expressing ras oncogene but not in other fibroblasts bradykinin mimicks the effect of growth factors on the cell membrane.
Highlights
Mean values f S.E. C, original recording from inside-out cell membrane patches a t different potentials; calcium activity 1 p ~pi,pette and bath 150 mM K+
From the Institute for Physiology and the §Institute for Biochemistry, Universityof Innsbruck, Fritz-Pregl-Strasse3, A-6010 Innsbruck, Austria
To test for functional genes are resistant to inactivatiobny GTPase-activating proconsequences of ras oncogene expression, electrophys- tein (McCormick, 1989)
Summary
Mean values f S.E. C, original recording from inside-out cell membrane patches a t different potentials; calcium activity 1 p ~pi,pette and bath 150 mM K+. As were due to activationofK' channels, extracellular K' con- illustrated, bradykinin led to a transient increase of centration was enhanced from 5.4 to 20 mM, which reduced intracellular calcium.
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