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Cyclic ADP-ribose (cADPR) is a natural compound that mobilizes calcium ions in several eukaryotic cells. Although it can lead to the release of calcium ions in T lymphocytes, it has not been firmly established as a second messenger in these cells. Here, using high-performance liquid chromatography analysis, 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 antagonists. 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.

Original publication

DOI

10.1038/18024

Type

Journal article

Journal

Nature

Publication Date

04/03/1999

Volume

398

Pages

70 - 73

Keywords

Adenosine Diphosphate Ribose, Antigens, CD3, Calcium, Calcium Signaling, Chromatography, High Pressure Liquid, Cyclic ADP-Ribose, Enzyme Activation, Humans, Inositol 1,4,5-Trisphosphate, Jurkat Cells, Lymphocyte Activation, Ryanodine, Ryanodine Receptor Calcium Release Channel, Second Messenger Systems, T-Lymphocytes