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Ca2+ signals are probably the most common intracellular signaling cellular events, controlling an extensive range of responses in virtually all cells. Many cellular stimuli, often acting at cell surface receptors, evoke Ca2+ signals by mobilizing Ca2+ from intracellular stores. Inositol trisphosphate (IP3) was the first messenger shown to link events at the plasma membrane to release Ca2+ from the endoplasmic reticulum (ER), through the activation of IP3-gated Ca2+ release channels (IP3 receptors). Subsequently, two additional Ca2+ mobilizing messengers were discovered, cADPR and NAADP. Both are metabolites of pyridine nucleotides, and may be produced by the same class of enzymes, ADP-ribosyl cyclases, such as CD38. Whilst cADPR mobilizes Ca2+ from the ER by activation of ryanodine receptors (RyRs), NAADP releases Ca2+ from acidic stores by a mechanism involving the activation of two pore channels (TPCs). In addition, other pyridine nucleotides have emerged as intracellular messengers. ADP-ribose and 2'-deoxy-ADPR both activate TRPM2 channels which are expressed at the plasma membrane and in lysosomes.

Original publication




Journal article


Advances in experimental medicine and biology

Publication Date





371 - 394


Department of Pharmacology, University of Oxford, Oxford, UK.


Intracellular Space, Endoplasmic Reticulum, Animals, Humans, Calcium, Pyridines, NADP, Cyclic ADP-Ribose, Ryanodine Receptor Calcium Release Channel, Calcium Signaling