NAADP-Evoked Ca2+ Signaling: The DUOX2–HN1L/JPT2–Ryanodine Receptor 1 Axis

Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca2+ mobilizing second messenger known to date. Major steps elucidating metabolism and Ca2+ mobilizing activity of NAADP are reviewed, with emphasis on a novel redox cycle between the inactive reduced form, NAADPH, and the active oxidized form, NAADP. Oxidation from NAADPH to NAADP is catalyzed in cell free system by (dual) NADPH oxidases NOX5, DUOX1, and DUOX2, whereas reduction from NAADP to NAADPH is catalyzed by glucose 6-phosphate dehydrogenase. Using different knockout models for NOX and DUOX isozymes, DUOX2 was identified as NAADP forming enzyme in early T-cell activation.Recently, receptors or binding proteins for NAADP were identified: hematological and neurological expressed 1-like protein (HN1L)/Jupiter microtubule associated homolog 2 (JPT2) and Lsm12 are small cytosolic proteins that bind NAADP. In addition, they interact with NAADP-sensitive Ca2+ channels, such as ryanodine receptor type 1 (RYR1) or two-pore channels (TPC).Due to its role as Ca2+ mobilizing second messenger in T cells, NAADP's involvement in inflammation is also reviewed. In the central nervous system (CNS), NAADP regulates autoimmunity because NAADP antagonism affects a couple of T-cell migration and re-activation events, e.g. secretion of the pro-inflammatory cytokine interleukin-17. Further, the role of NAADP in transdifferentiation of IL-17-producing Th17 cells into T regulatory type 1 cells in vitro and in vivo is discussed.