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Suramin and Disulfonated Stilbene Derivatives Stimulate the Ca²⁺-Induced Ca²⁺-Release Mechanism in A7r5 Cells

Laboratorium voor Fysiologie, Katholieke Universiteit Leuven, Campus Gasthuisberg O/N, Leuven, Belgium

We have described previously a novel Ca²⁺-induced Ca²⁺-release (CICR) mechanism in permeabilized A7r5 cells (embryonic rat aorta) and 16HBE14o-cells (human bronchial mucosa) cells (J Biol Chem 278:27548–27555, 2003). This CICR mechanism was activated upon the elevation of the free cytosolic calcium concentration [Ca²⁺]_c and was not inhibited by pharmacological inhibitors of the inositol-1,4,5-trisphosphate (IP₃) receptor nor of the ryanodine receptor. This CICR mechanism was inhibited by calmodulin (CaM)₁₂₃₄, a Ca²⁺-insensitive CaM mutant, and by different members of the superfamily of CaM-like Ca²⁺-binding proteins. Here, we present evidence that the CICR mechanism that is expressed in A7r5 and 16HBE14o-cells is strongly activated by suramin and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS). We found several indications that both activation mechanisms are indeed two different modes of the same release system. Suramin/DIDS-induced Ca²⁺ release was only detected in cells that displayed the CICR mechanism, and cell types that do not express this type of CICR mechanism did not exhibit suramin/DIDS-induced Ca²⁺ release. Furthermore, we show that the suramin-stimulated Ca²⁺ release is regulated by Ca²⁺ and CaM in a similar way as the previously described CICR mechanism. The pharmacological characterization of the suramin/DIDS-induced Ca²⁺ release further confirms its properties as a novel CaM-regulated Ca²⁺-release mechanism. We also investigated the effects of disulfonated stilbene derivatives on IP₃-induced Ca²⁺ release and found, in contrast to the effect on CICR, a strong inhibition by DIDS and 4'-acetoamido-4'-isothiocyanostilbene-2',2'-disulfonic acid.

Address correspondence to: Dr. Humbert De Smedt, Laboratorium voor Fysiologie, Katholieke Universiteit Leuven Campus Gasthuisberg Herestraat 49/802, B-3000 Leuven, Belgium. E-mail: humbert.desmedt{at}med.kuleuven.ac.be

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