Mechanism and biological significance of the Ha-ras-induced activation of the Na+/H(+)-antiporter.
Expression of the transforming Ha-ras oncogene in MMTV-LTR transfected NIH 3T3 cells leads to a growth factor independent activation of the Na+/H(+)-antiporter. The activation of the antiporter is insensitive to the protein kinase inhibitor staurosporine and equally expressed in protein kinase C-depleted cells. It is concluded that the Ha-ras induced activation of the antiporter occurs by a protein kinase C-independent mechanism. An inhibition of the Na+/H(+)-antiporter by dimethylamiloride or a reduction of the extracellular [Na+] concentration results in a depression of the bombesin induced release of Ca2+ from intracellular stores. These results are explained by a steep pH-dependence of the Ca2(+)-mobilizing system which exhibits a maximum at pH 7.1 in the system studied here. Stimulation by growth factors of quiescent cells with a resting pH below 7 results in a shift of the cytosolic pH towards the optimum for the Ca2+ release. In agreement with the proposed interrelationship, pHi and [Ca2+]i rise and peak simultaneously after addition of bombesin to G0 arrested cells.
Maly
K
K
Institute for Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
Hochleitner
B
B
Uberall
F
F
Loferer
H
H
Oberhuber
H
H
Doppler
W
W
Grunicke
H
H
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001839:Bombesin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D011905:Genes, ras; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D017923:Sodium-Hydrogen Exchangers; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection
D000470:Alkaloids; D002352:Carrier Proteins; D017923:Sodium-Hydrogen Exchangers; D003907:Dexamethasone; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate; D001839:Bombesin; D002118:Calcium