Washing out of lipophilic compounds induces a transient increase in the passive Ca(2+) leak in permeabilized A7r5 cells.
We have investigated how the immunosuppressant drug FK506 affected the basal Ca(2+) leak in permeabilized A7r5 cells. Non-mitochondrial Ca(2+) stores loaded to steady state with Ca(2+) slowly lost their accumulated Ca(2+) during incubation in a Ca(2+)-free efflux medium. FK506 up to 100 microM had no effect on the basal Ca(2+) leak. In contrast, the rate of Ca(2+) release proceeded much faster immediately after washing out FK506. The increase in rate of Ca(2+) release after washing out of this compound depended on both its initial concentration and on the time of pre-incubation. A similar effect was also observed after removing another immunosuppressant drug (rapamycin) and after removing the inositol 1,4,5-trisphosphate receptor inhibitor xestospongin C. Since all these substances have a high octanol/H(2)O partition coefficient and accumulate in the endoplasmic reticulum membrane, we suggest that the transient increase in the basal Ca(2+) leak is due to the sudden removal of these lipophilic substances from the membrane.
Bultynck
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Laboratorium voor Fysiologie, K.U.Leuven Campus Gasthuisberg O/N, Herestraat 49, B-3000 Leuven, Belgium. geert.bultynck@med.kuleuven.ac.be
De Smedt
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H
Parys
J B
JB
Callewaert
G
G
Missiaen
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L
D000818:Animals; D001011:Aorta; D002118:Calcium / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000187:drug effects* / Q000378:metabolism; D047028:Macrocyclic Compounds; D008563:Membrane Lipids / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology; D051381:Rats; D020123:Sirolimus / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D007166:Immunosuppressive Agents; D047028:Macrocyclic Compounds; D008563:Membrane Lipids; D010080:Oxazoles; C108644:xestospongin A; D002118:Calcium; D020123:Sirolimus; D016559:Tacrolimus