+, NAD+ Precursors and NAD+-Derived Signal Metabolites and Second Messengers: Old and New Topological Paradoxes
Subcellular and Intercellular Traffic of NAD
NAD+ metabolism and regulation are still incompletely defined in their features. Specifically, several compartmentation problems, both subcellular and intercellular, have emerged in the past years. A topological paradox was identified in the CD38/NAD+/Cyclic ADP-ribose
system which represents a means for achieving regulation of intracellular Calcium levels ([Ca2+]i and of Ca2+-mediated cell functions. CD38, an ectoenzyme featuring ADP-ribosyl cyclase (ADPRC) activity, is known to catalyze the generation of as many as eight
Ca2+-active signal metabolites, including cADPR, ADPR, NAADP and three adenine homodinucleotides (Ap2A and two isomers thereof, designated P18 and P24). The first paradox concerns the ectocellular conversion of NAD+ to cADPR and the intracellular activity of cADPR as
a potent Ca2+ mobilizer from stores expressing ryanodine receptors/channels on the endoplasmic/sarcoplasmic reticulum. This topological inconsistency was solved with the identification of hexameric Connexin 43 hemichannels (Cx43 HC) as an equilibrative transport system for NAD+,
and of redundant equilibrative, and especially concentrative, transport systems for cADPR. Other transporters for NAADP+, P18 and P24 are still unknown. In addition, NAD+ itself and some of its derivatives were recognized to be agonists of purinergic receptors, e.g.,
P2Y11 and P2X7, thereby affecting the [Ca2+]i levels either through protein kinase A- and phospholipase C-mediated pathways or through direct influx of extracellular Ca2+, respectively. Finally, recent findings demonstrate that the enzymes
involved in NAD+ biosynthesis and some of the enzymes involved in the multiple pathways of NAD+ utilization localize to distinct subcellular compartments of the same cell and, surprisingly, also to different cell types of the same organism. Therefore, NAD+
biosynthesis from several precursors, collectively defined Vitamin B3 forms, is at the same time an organismal and a cellular process, whose individual steps may occur in different cells/tissues/organs. Thus, a paracrine crosstalk is activated via the exchange of intermediate metabolites in
biological fluids (e.g., Nicotinamide mononucleotide and Nicotinamide riboside), and the eventual NAD+ biosynthesis occurs in selected cells able to utilize it for the display of diverse, fundamental cell functions. These are driven by NAD+-consuming enzymes, as ADPRCs,
mono ADP-ribosyltransferases, poly(ADP-ribose) polymerases and different sirtuins (NAD+-dependent protein deacetylases).
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The MESSENGER is an international peer-reviewed journal, focused on all aspects of messenger-signaling. The MESSENGER is devoted to all aspects of messenger- signaling, from the upstream activation of the receptors of the first messengers to the downstream signaling cascades. Undoubtedly, more novel second messengers will be discovered, expanding the scope of the journal appropriately. The MESSENGER publishes review articles, full research articles and short communications of important new scientific findings on all research aspects of messengers.
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