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J. Biol. Chem., Vol. 278, Issue 30, 27548-27555, July 25, 2003

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A Novel Ca²⁺-induced Ca²⁺ Release Mechanism in A7r5 Cells Regulated by Calmodulin-like Proteins^*

Nael Nadif Kasri  , Ilse Sienaert  ¶, Jan B. Parys , Geert Callewaert , Ludwig Missiaen , Andreas Jeromin || and Humbert De Smedt  **

From the Laboratorium voor Fysiologie, K.U. Leuven Campus Gasthuisberg O/N, Herestraat 49, B-3000 Leuven, Belgium and the ^||Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030

Intracellular Ca²⁺ release is involved in setting up Ca²⁺ signals in all eukaryotic cells. Here we report that an increase in free Ca²⁺ concentration triggered the release of up to 41 ± 3% of the intracellular Ca²⁺ stores in permeabilized A7r5 (embryonic rat aorta) cells with an EC₅₀ of 700 nM. This type of Ca²⁺-induced Ca²⁺ release (CICR) was neither mediated by inositol 1,4,5-trisphosphate receptors nor by ryanodine receptors, because it was not blocked by heparin, 2-aminoethoxydiphenyl borate, xestospongin C, ruthenium red, or ryanodine. ATP dose-dependently stimulated the CICR mechanism, whereas 10 mM MgCl₂ abolished it. CICR was not affected by exogenously added calmodulin (CaM), but CaM₁₂₃₄, a Ca²⁺-insensitive CaM mutant, strongly inhibited the CICR mechanism. Other proteins of the CaM-like neuronal Ca²⁺-sensor protein family such as Ca²⁺-binding protein 1 and neuronal Ca²⁺ sensor-1 were equally potent for inhibiting the CICR. Removal of endogenous CaM, using a CaM-binding peptide derived from the ryanodine receptor type-1 (amino acids 3614–3643) prevented subsequent activation of the CICR mechanism. A similar CICR mechanism was also found in 16HBE14o-(human bronchial mucosa) cells. We conclude that A7r5 and 16HBE14o-cells express a novel type of CICR mechanism that is silent in normal resting conditions due to inhibition by CaM but becomes activated by a Ca²⁺-dependent dissociation of CaM. This CICR mechanism, which may be regulated by members of the family of neuronal Ca²⁺-sensor proteins, may provide an additional route for Ca²⁺ release that could allow amplification of small Ca²⁺ signals.

Received for publication, February 26, 2003 , and in revised form, April 18, 2003.

^* This work was supported in part by Grants 1.5.112.02 (to I. S.), G.0210.03 (to H. D. S. and J. B. P.), and G.O206.01 (to L. M.) from the Fund for Scientific Research Flanders (Belgium); by Grant 99/08 from the Concerted Actions of the K.U. Leuven (to L. M., H. D. S., G. C., and J. B. P.); and by the Interuniversity Poles of Attraction Program-Belgian State, Prime Minister's Office, Federal Office for Scientific, Technical, and Cultural Affairs (Grant IUAP P5/05). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ A postdoctoral fellow of the Fund for Scientific Research Flanders (Belgium).

To whom correspondence may be addressed. Tel.: 32-16-34-58-34; Fax: 32-16-34-59-91; E-mail: nael.nadifkasri{at}med.kuleuven.ac.be.

^** To whom correspondence may be addressed. Tel.: 32-16-34-57-25; Fax: 32-16-34-59-91; E-mail: humbert.desmedt{at}med.kuleuven.ac.be.

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