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

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.

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Figure 1: Endogenous cADPR, ADP-ribosyl cyclase activation and [Ca2+]i in response to stimulation of the TCR/CD3 complex.
Figure 2: Inhibition of long-lasting Ca2+ signalling by 7-deaza-8-Br-cADPR.
Figure 3: Effect of antagonists against Ins(1, 4, 5)P3 and cADPR on Ca2+ signalling in single Jurkat T cells.
Figure 4: Expression of ryanodine receptor in Jurkat T-lymphocytes.
Figure 5: Effect of cADPR on [3H]ryanodine binding to P10 membranes.

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Acknowledgements

We thank M. K. Jacobson and K.-H. Krause for comments on the manuscript, and V.C. Bailey and S. J. Mills for synthesizing some of the ligands used. This work was supported by the Deutsche Forschungsgemeinschaft (A.H.G., G.W.M. and H.S.-K.), Alexander-von-Humboldt-Stiftung (C.P.S.), Büro zur Förderung von Auslandsbeziehungen and Östereichische Nationalbank (M.H.) and the Wellcome Trust (B.V.L.P. and A.H.G.).

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Guse, A., da Silva, C., Berg, I. et al. Regulation of calcium signalling in T lymphocytes by the second messenger cyclic ADP-ribose. Nature 398, 70–73 (1999). https://doi.org/10.1038/18024

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