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 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.

NAADP-mediated Ca 2+ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist

“…NAADP mediated Ca 2ϩ release starts rapidly within a few seconds upon TCR/CD3 ligation (8). By contrast, InsP 3 -and cADPRmediated releases appear within a few minutes (39) or within tens of minutes, respectively (6). A possible reason for this complex regulatory Ca 2ϩ release network may be the need for temporal checkpoints, at which the T cell, based upon the input via the TCR/CD3 complex and diverse co-receptors, can control whether to proceed with activation or not (40).…”

Involvement of P2X receptors in the NAD+-induced rise in [Ca2+]i in human monocytes

“…Beyond their central roles in energy metabolism, they serve as substrates for extracellular enzymes, giving rise to the generation of metabolites that themselves exhibit signaling functions [39]. Well-known biologically active metabolites of ATP are AMP and adenosine, whereas degradation of NAD + yields cADPR and NAADP [3], two second messengers that induce release of calcium from intracellular stores [40,41]. However, whereas ATP per se has been shown to function through the specific activation of purinergic receptors (P2X and P2Y), there is hardly any information about surface receptors triggering intracellular events induced by intact NAD + .…”

Kinetic competence of the cADP-ribose‒CD38 complex as an intermediate in the CD38/NAD+ glycohydrolase-catalysed reactions: implication for CD38 signalling

“…In these cases, the catalysed conversion of NAD + is accompanied by a transient formation of cADPR (up to 50 % of the reaction products ; see, for example, [31]), which is ultimately turned-over in favour of ADP-ribose. Such observations are of importance because they point to the possible occurrence of different members of a CD38 family which can be distinguished by their catalytic properties with regard to the formation and eventual hydrolysis of cADPR and probably also by their (sub)cellular\ tissular localization (see also, for example, [34][35][36]). …”