Interference of Ha-ras with inositol trisphosphate-mediated Ca2+-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 Ca2+-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 Ca2+-release by IP3 in permeabilized cells. The IP3 concentration required for half-maximal Ca2+-release is doubled in Ha-ras expressing cells. Maximal Ca2+-release which is obtained with 2,μM IP3 in control cells requires 10μM IP3 in cells expressing Ha-ras. The desensitization of the IP3 receptors coincides with the desensitization of the Ca2+-mobilizing system to bombesin. The results indicate that the Ha-ras mediated desensitization of the Ca2+-releasing system to bombesin is — at least in part — caused by a decrease in the affinity of the IP3 receptor to inositol trisphosphate.