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

Cyclic ADP-ribose (cADPR) is a natural compound that mobilizes calcium ions in several eukaryotic cells(1-3). Although it can lead to the release of c alcium ions in T lymphocytes(4-7), it has not been firmly established as a second messenger in these cells. Here, using high-performance liquid chroma tography analysis(8), 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 r elation between increased cADPR concentrations, sustained calcium signallin g and activation of T cells, as shown by inhibition of TCR/CD3-stimulated c alcium sig-nailing, cell proliferation and expression of the early- and lat e-activation markers I CD25 and HLA-DR by using cADPR antagonists(9). The m olecular target for cADPR, the type-3 ryanodine receptor/calcium channel, i s expressed in T cells. Increased cADPR significantly and specifically stim ulates the apparent association of [H-3]ryanodine with the type-3 ryanodine receptor, indicating a direct modulatory effect of cADPR on channel openin g. Thus we show the presence, causal relation and biological significance o f the major constituents of the cADPR/calcium-signalling pathway in human T cells.