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Published online 7 August 2000. doi:10.1083/jcb.150.3.581
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© The Rockefeller University Press, 0021-9525/2000/8/581/ $5.00
The Journal of Cell Biology, Volume 150, Number 3, August 7, 2000 581-588

Original Article

Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP+) Is an Essential Regulator of T-lymphocyte Ca2+-signaling

Ingeborg Berga, Barry V.L. Potterb, Georg W. Mayra, and Andreas H. Gusea
a Institute of Medical Biochemistry and Molecular Biology, Division of Cellular Signal Transduction, University of Hamburg, D-20146 Hamburg, Germany
b Wolfson Laboratory for Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom

Correspondence to: Andreas H. Guse, University of Hamburg, Institute for Medical Biochemistry and Molecular Biology, Div. Cellular Signal Transduction, Grindelallee 117, IV, D-20146 Hamburg, Germany. Tel:49-40-42838-4276 Fax:49-40-42838-4275 E-mail:guse{at}uke.uni-hamburg.de.

Microinjection of human Jurkat T-lymphocytes with nicotinic acid adenine dinucleotide phosphate (NAADP+) dose-dependently stimulated intracellular Ca2+-signaling. At a concentration of 10 nM NAADP+ evoked repetitive and long-lasting Ca2+-oscillations of low amplitude, whereas at 50 and 100 nM, a rapid and high initial Ca2+-peak followed by trains of smaller Ca2+-oscillations was observed. Higher concentrations of NAADP+ (1 and 10 µM) gradually reduced the initial Ca2+-peak, and a complete self-inactivation of Ca2+-signals was seen at 100 µM. The effect of NAADP+ was specific as it was not observed with nicotinamide adenine dinucleotide phosphate. Both inositol 1,4,5-trisphosphate– and cyclic adenosine diphosphoribose–mediated Ca2+-signaling were efficiently inhibited by coinjection of a self-inactivating concentration of NAADP+. Most importantly, microinjection of a self-inactivating concentration of NAADP+ completely abolished subsequent stimulation of Ca2+-signaling via the T cell receptor/CD3 complex, indicating that a functional NAADP+ Ca2+-release system is essential for T-lymphocyte Ca2+-signaling.

Key Words: cyclic ADP-ribose, inositol 1,4,5-trisphosphate, T cell activation, signal transduction, ryanodine receptor


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