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

doi:10.1083/jcb.150.3.581

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 Berg^a, Barry V.L. Potter^b, Georg W. Mayr^a, and Andreas H. Guse^a
^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 nicotinicacid adenine dinucleotide phosphate (NAADP⁺) dose-dependentlystimulated intracellular Ca²⁺-signaling. At a concentrationof 10 nM NAADP⁺ evoked repetitive and long-lasting Ca²⁺-oscillationsof low amplitude, whereas at 50 and 100 nM, a rapid and highinitial Ca²⁺-peak followed by trains of smaller Ca²⁺-oscillationswas observed. Higher concentrations of NAADP⁺ (1 and 10 µM)gradually reduced the initial Ca²⁺-peak, and a complete self-inactivationof Ca²⁺-signals was seen at 100 µM. The effect of NAADP⁺was specific as it was not observed with nicotinamide adeninedinucleotide phosphate. Both inositol 1,4,5-trisphosphate–and cyclic adenosine diphosphoribose–mediated Ca²⁺-signalingwere efficiently inhibited by coinjection of a self-inactivatingconcentration of NAADP⁺. Most importantly, microinjection ofa self-inactivating concentration of NAADP⁺ completely abolishedsubsequent stimulation of Ca²⁺-signaling via the T cell receptor/CD3complex, indicating that a functional NAADP⁺ Ca²⁺-release systemis 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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