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

Nature. 1999 Mar 4;398(6722):70-3. doi: 10.1038/18024.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate Ribose / analogs & derivatives*
  • Adenosine Diphosphate Ribose / antagonists & inhibitors
  • Adenosine Diphosphate Ribose / metabolism
  • Adenosine Diphosphate Ribose / pharmacology
  • CD3 Complex / immunology
  • CD3 Complex / metabolism
  • Calcium / metabolism*
  • Calcium Signaling*
  • Chromatography, High Pressure Liquid
  • Cyclic ADP-Ribose
  • Enzyme Activation
  • Humans
  • Inositol 1,4,5-Trisphosphate / antagonists & inhibitors
  • Inositol 1,4,5-Trisphosphate / metabolism
  • Jurkat Cells
  • Lymphocyte Activation
  • Ryanodine / metabolism
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • Second Messenger Systems*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*


  • 7-deaza-8-bromo-cyclic ADP-ribose
  • CD3 Complex
  • Ryanodine Receptor Calcium Release Channel
  • Cyclic ADP-Ribose
  • Ryanodine
  • Adenosine Diphosphate Ribose
  • Inositol 1,4,5-Trisphosphate
  • Calcium