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J. Biol. Chem., Vol. 282, Issue 26, 18864-18871, June 29, 2007

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NAADP Mobilizes Calcium from the Endoplasmic Reticular Ca²⁺ Store in T-lymphocytes^*

From the Calcium Signaling Group, University Medical Centre Hamburg-Eppendorf, Centre of Experimental Medicine, Institute of Biochemistry and Molecular Biology I, Cellular Signal Transduction, Martinistrasse 52, D-20426 Hamburg, Germany

The target calcium store of nicotinic acid adenine dinucleotide phosphate (NAADP), the most potent endogenous calcium-mobilizing compound known to date, has been proposed to reside in the lysosomal compartment or in the endo/sarcoplasmic reticulum. This study was performed to test the hypothesis of a lysosomal versus an endoplasmic reticular calcium store sensitive to NAADP in T-lymphocytes. Pretreatment of intact Jurkat T cells with glycyl-phenylalanine 2-naphthylamide largely reduced staining of lysosomes by LysoTracker Red and abolished NAADP-induced Ca²⁺ signaling. However, the inhibitory effect was not specific since Ca²⁺ mobilization by D-myo-inositol 1,4,5-trisphosphate and cyclic ADP-ribose was abolished, too. Bafilomycin A1, an inhibitor of the lysosomal H⁺-ATPase, did not block or reduce NAADP-induced Ca²⁺ signaling, although it effectively prevented labeling of lysosomes by LysoTracker Red. Further, previous T cell receptor/CD3 stimulation in the presence of bafilomycin A1, assumed to block refilling of lysosomal Ca²⁺ stores, did not antagonize subsequent NAADP-induced Ca²⁺ signaling. In contrast to bafilomycin A1, emptying of the endoplasmic reticulum by thapsigargin almost completely prevented Ca²⁺ signaling induced by NAADP. In conclusion, in T-lymphocytes, no evidence for involvement of lysosomes in NAADP-mediated Ca²⁺ signaling was obtained. The sensitivity of NAADP-induced Ca²⁺ signaling toward thapsigargin, combined with our recent results identifying ryanodine receptors as the target calcium channel of NAADP (Dammermann, W., and Guse, A. H. (2005) J. Biol. Chem. 280, 21394–21399), rather suggest that the target calcium store of NAADP in T cells is the endoplasmic reticulum.

Received for publication, November 27, 2006 , and in revised form, April 19, 2007.

^* This work was supported by the Deutsche Forschungsgemeinschaft Grants GU 360/7-3 and 7-5 (to A. H. G.) and the Gemeinnützige Hertie-Stiftung Grants 1.01.1/04/010 and 1.01.1/07/005 (to A. H. G.). 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.

¹ Supported by a stipend from the Studienstiftung des Deutschen Volkes.

² To whom correspondence should be addressed. Tel.: 49-40-42803-2828; Fax: 49-40-42803-9880; E-mail: guse{at}uke.uni-hamburg.de.

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