Regulation of calcium signalling in T lymphocytes by the second messenger cyclic ADP-ribose

Andreas H. Guse (), Cristina P. da Silva, Ingeborg Berg, Alla L. Skapenko, Karin Weber, Petra Heyer, Martin Hohenegger, Gloria A. Ashamu, Hendrik Schulze-Koops, Barry V. L. Potter and Georg W. Mayr
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Andreas H. Guse: Institute of Physiological Chemistry, University of Hamburg
Cristina P. da Silva: Institute of Physiological Chemistry, University of Hamburg
Ingeborg Berg: Institute of Physiological Chemistry, University of Hamburg
Alla L. Skapenko: University of Erlangen-Nürnberg
Karin Weber: Institute of Physiological Chemistry, University of Hamburg
Petra Heyer: Institute of Physiological Chemistry, University of Hamburg
Martin Hohenegger: Institute of Pharmacology, University of Vienna
Gloria A. Ashamu: Wolfson Laboratory for Medicinal Chemistry, University of Bath
Hendrik Schulze-Koops: University of Erlangen-Nürnberg
Barry V. L. Potter: Wolfson Laboratory for Medicinal Chemistry, University of Bath
Georg W. Mayr: Institute of Physiological Chemistry, University of Hamburg

Nature, 1999, vol. 398, issue 6722, 70-73

Abstract: Abstract Cyclic ADP-ribose (cADPR) is a natural compound that mobilizes calcium ions in several eukaryotic cells1,2,3. Although it can lead to the release of calcium ions in T lymphocytes4,5,6,7, it has not been firmly established as a second messenger in these cells. Here, using high-performance liquid chromatography analysis8, we show that stimulation of the T-cell receptor/CD3 (TCR/CD3) complex results in activation of a soluble ADP-ribosyl cyclase and a sustained increase in intracellular levels of cADPR. There is a causal relation between increased cADPR concentrations, sustained calcium signalling and activation of T cells, as shown by inhibition of TCR/CD3-stimulated calcium signalling, cell proliferation and expression of the early- and late-activation markers CD25 and HLA-DR by using cADPR antagonists9. The molecular target for cADPR, the type-3 ryanodine receptor/calcium channel, is expressed in T cells. Increased cADPR significantly and specifically stimulates the apparent association of [3H]ryanodine with the type-3 ryanodine receptor, indicating a direct modulatory effect of cADPR on channel opening. Thus we show the presence, causal relation and biological significance of the major constituents of the cADPR/calcium-signalling pathway in human T cells.

Date: 1999
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DOI: 10.1038/18024

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