A novel Ca2+-induced Ca2+ release mechanism in A7r5 cells regulated by calmodulin-like proteins

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Abstract

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.

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Kasri, N. N., Sienaert, I., Parys, J. B., Callewaert, G., Missiaen, L., Jeromin, A., & De Smedt, H. (2003). A novel Ca2+-induced Ca2+ release mechanism in A7r5 cells regulated by calmodulin-like proteins. Journal of Biological Chemistry, 278(30), 27548–27555. https://doi.org/10.1074/jbc.M302026200

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