Mechanism of desensitization of the Ca2(+)-mobilizing system to bombesin by Ha-ras. Independence from down-modulation of agonist-stimulated inositol phosphate production.
Expression of a transforming Ha-ras gene in NIH 3T3 cells transfected with an inducible Ha-ras construct leads to a rapid desensitization of the intracellular Ca2(+)-mobilizing system to bombesin and serum growth factors. Half-maximal depression of the Ca2+ response is observed 2 h after induction of p21ras. A maximum is obtained after 6 h. Bombesin-induced elevation of inositol 1,4,5-trisphosphate formation is also depressed in cells expressing Ha-ras. This, however, is a relatively late phenomenon and not yet detectable when maximal depression of the Ca2+ signal is observed. We conclude that the rapid densensitization of the Ca2(+)-releasing system to bombesin by Ha-ras is not caused by down-modulation or uncoupling of phospholipase C-coupled bombesin receptors. The inositol 1,4,5-trisphosphate-mediated release of intracellular Ca2+ is reduced in permeabilized cells expressing the Ha-ras oncogene. A depletion of intracellular Ca2+ stores by Ha-ras is unlikely since (i) the Ha-ras-induced growth factor-independent stimulation of inositol phosphate formation occurs several hours after reduction of the Ca2+ response and (ii) the Ca2+ load of intracellular nonmitochondrial Ca2+ stores was found to be unaffected by Ha-ras. We conclude that the desensitization of the Ca2(+)-mobilizing system is caused either by partial inhibition of inositol 1,4,5-trisphosphate-regulated Ca2+ channels or by interference of Ha-ras with Ca2+ translocation between intracellular Ca2+ compartments.
Oberhuber
H
H
Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
Maly
K
K
Uberall
F
F
Hoflacher
J
J
Kiani
A
A
Grunicke
H H
HH
D000818:Animals; D001839:Bombesin / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D015220:Calcium Channels / Q000502:physiology; D002451:Cell Compartmentation; D002460:Cell Line; D015870:Gene Expression; D011905:Genes, ras; D015544:Inositol 1,4,5-Trisphosphate / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000502:physiology*; D010716:Phosphatidylinositols / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D011519:Proto-Oncogenes; D015398:Signal Transduction
D015220:Calcium Channels; D010716:Phosphatidylinositols; D000001:Calcimycin; D015544:Inositol 1,4,5-Trisphosphate; D015689:Oncogene Protein p21(ras); D016283:Proto-Oncogene Proteins p21(ras); D001839:Bombesin; D002118:Calcium