Interference of Ha-ras with inositol trisphosphate-mediated Ca(2+)-release.
Expression of a transforming Ha-ras by dexamethasone in NIH3T3 cells transfected with a glucocorticoid-inducible Ha-ras construct results in a rapid desensitization of the intracellular Ca(2+)-mobilizing system to bombesin. This effect precedes the down-modulation of inositol trisphosphate (IP3) formation by several hours and is, therefore, not explained by an uncoupling of phosphoinositidase C. It is demonstrated that expression of Ha-ras attenuates the Ca(2+)-release by IP3 in permeabilized cells. The IP3 concentration required for half-maximal Ca(2+)-release is doubled in Ha-ras expressing cells. Maximal Ca(2+)-release which is obtained with 2 microM IP3 in control cells requires 10 microM IP3 in cells expressing Ha-ras. The desensitization of the IP3 receptors coincides with the desensitization of the Ca(2+)-mobilizing system to bombesin. The results indicate that the Ha-ras mediated desensitization of the Ca(2+)-releasing system to bombesin is--at least in part--caused by a decrease in the affinity of the IP3 receptor to inositol trisphosphate.
Maly
K
K
Institute of Medical Chemistry and Biochemistry, Innsbruck, Austria.
Kiani
A
A
Oberhuber
H
H
Grunicke
H
H
D016475:3T3 Cells; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels; D002463:Cell Membrane Permeability; D003907:Dexamethasone / Q000494:pharmacology; D011905:Genes, ras; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007700:Kinetics; D051379:Mice; D011956:Receptors, Cell Surface / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D014162:Transfection
D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D003907:Dexamethasone; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium