Pyridine Nucleotide Metabolites and Calcium Release from Intracellular Stores

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.