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J. Biol. Chem., Vol. 281, Issue 25, 16906-16913, June 23, 2006

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Second Messenger Function of Nicotinic Acid Adenine Dinucleotide Phosphate Revealed by an Improved Enzymatic Cycling Assay^*

From the Calcium Signalling Group, Institute of Biochemistry and Molecular Biology I: Cellular Signal Transduction, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany

Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent activator of Ca²⁺ release from intracellular stores known today. Although recent reports have suggested an important function of NAADP in human T lymphocytes, direct evidence for receptor-induced formation of NAADP is yet missing in these cells. Thus, we developed a highly sensitive and specific enzyme assay capable of quantifying low fmol amounts of NAADP. In unstimulated T cells, the NAADP concentration amounted to 4.4 ± 1.6 nM (0.055 ± 0.028 pmol/mg of protein). Stimulation of the cells via the T cell receptor/CD3 complex resulted in biphasic elevation kinetics of cellular NAADP levels and was characterized by a bell-shaped concentration-response curve for NAADP. In contrast, the NAADP concentration was elevated neither upon activation of the ADP-ribose/TRPM2 channel Ca²⁺ signaling system nor by an increase of the intracellular Ca²⁺ concentration upon thapsigargin stimulation. T cell receptor/CD3 complex-mediated NAADP formation was dependent on the activity of tyrosine kinases because genistein completely blocked NAADP elevation. Thus, we propose a regulated formation of NAADP upon specific stimulation of the T cell receptor/CD3 complex, suggesting a function of NAADP as a Ca²⁺-mobilizing second messenger during T cell activation.

Received for publication, February 13, 2006 , and in revised form, April 19, 2006.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants GU 360/7-3, 9-1, 9-2, and 10-1 (to A. H. G.), the Gemeinnützige Hertie-Stiftung (to A. H. G.), and the Wellcome Trust (to A. H. G.). This article is based in part on doctoral studies (by A. G. and S. B.) in the departments of Chemistry and Biology, University of Hamburg. 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 Both authors made equal contributions to this work.

² To whom correspondence should be addressed: University Medical Center Hamburg-Eppendorf, Center of Experimental Medicine, Inst. of Biochemistry and Molecular Biology I: Cellular Signal Transduction, Martinistrasse 52, D-20246 Hamburg, Germany. Tel.: 49-40-42803-2828; Fax: 49-40-42803-9880; E-mail: guse{at}uke.uni-hamburg.de.

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