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J. Biol. Chem. 278 (16): 13672-13679

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

R-Ras Alters Ca2+ Homeostasis by Increasing the Ca2+ Leak across the Endoplasmic Reticular Membrane*

Werner J. H. KoopmanDagger §, Remko R. BoschDagger §, Sjenet E. van Emst-de VriesDagger , Marcel Spaargaren||, Jan Joep H. H. M. De PontDagger , and Peter H. G. M. WillemsDagger **

From the Dagger  Department of Biochemistry, Nijmegen Center for Molecular Life Sciences, Nijmegen NL-6500 HB and the || Department of Pathology, Academic Medical Center, Amsterdam Zuidoost 1105 AZ, The Netherlands

Evidence in the literature implicating both Ras-like Ras (R-Ras) and intracellular Ca2+ in programmed cell death and integrin-mediated adhesion prompted us to investigate the possibility that R-Ras alters cellular Ca2+ handling. Chinese hamster ovary cells expressing the cholecystokinin (CCK)-A receptor were loaded with indo-1 to study the effects of constitutively active V38R-Ras and dominant negative N43R-Ras on the kinetics of the thapsigargin (Tg)- and CCK8-induced Ca2+ rises using high speed confocal microscopy. In the absence of extracellular Ca2+, both 1 µM Tg, a potent and selective inhibitor of the Ca2+ pump of the intracellular Ca2+ store, and 100 nM CCK8 evoked a transient rise in Ca2+, the size of which was decreased significantly after expression of V38R-Ras. At 0.1 nM, CCK8 evoked periodic Ca2+ rises. The frequency of these Ca2+ oscillations was reduced significantly in V38R-Ras-expressing cells. In contrast to V38R-Ras, N43R-Ras did not alter the kinetics of the Tg- and CCK8-induced Ca2+ rises. The present findings are compatible with the idea that V38R-Ras expression increases the passive leak of Ca2+ of the store leading to a decrease in Ca2+ content of this store, which, in turn, leads to a decrease in frequency of the CCK8-induced cytosolic Ca2+ oscillations. The effect of V38R-Ras on the Ca2+ content of the intracellular Ca2+ store closely resembles that of the antiapoptotic protein Bcl-2 observed earlier. Together with reports on the role of dynamic Ca2+ changes in integrin-mediated adhesion, this leads us to propose that the reduction in endoplasmic reticulum Ca2+ content may underlie the antiapoptotic effect of R-Ras, whereas the decrease in frequency of stimulus-induced Ca2+ oscillations may play a role in the inhibitory effect of R-Ras on stimulus-induced cell detachment and migration.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors contributed equally to this work.

Supported by a grant from the Netherlands Organization for Scientific Research.

** To whom correspondence should be addressed: 160 Biochemistry NCMLS, University Medical Centre, Nijmegen University, P.O. Box 9101, Nijmegen NL-6500 HB, The Netherlands. Tel.: 31-24-361-4589; Fax: 31-24-354-0525; E-mail:

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

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