Figure 3.

eNAD and enzymatic/functional extracellular machinery in regulating immune responses. Extracellular NAD can also be metabolized by a series of enzymes of the cell surface that are involved in scavenging of nucleotides. The end product of the reaction, adenosine, can then be internalized and reconverted to related nucleosides (e.g., ATP or NAD). In particular, CD38 hydrolyzes NAD to generate intermediates (cADPR and ADPR), potent intracellular Ca²⁺-mobilizing agents, through binding RyR or TRPM2 receptors. CD38 activation induces migration, proliferation, and modulation of immune responses, specifically T cell functions, as detailed in the text. In addition, CD38 activity releases nicotinamide (the main NAD precursor) that can be internalized into the cell and, together with a second precursor nicotinic acid, converted in NAD by NAMPT and NAPRT activities, respectively, increasing intracellular NAD levels and affecting sirtuins and PARPs (NAD-consuming enzymes) functions. NAMPT and NAPRT can be secreted/released in the extracellular space acting as cytokine-like proteins. Finally, NAD and ATP can be converted in adenosine. ATP is metabolized by CD39 to AMP that is further hydrolyzed by ecto-5’-nucleotidase/CD73 which promotes the formation of adenosine. Adenosine then activates adenosine receptors (purinergic receptor P1). The final outcome depends on the relative concentrations of substrates and products and on the expression of nucleotide-metabolizing ecto-enzymes and NAD-biosynthetic enzymes. NAD, nicotinamide adenine dinucleotide; NADP, NAD phosphate; NAMPT, nicotinamide phosphoribosyltransferase; NAPRT, nicotinate phosphoribosyltransferase; PARPs, poly ADP-ribose polymerases; ADPR, ADP ribose; cADPR, cyclic ADP ribose; NAADP, nicotinic acid adenine dinucleotide phosphate; ATP, adenosine triphosphate; AMP, adenosine monophosphate; P1, adenosine purinergic receptor; RYR, ryanodine receptors; TRPM2, transient receptor potential melastatin-related 2; i, intracellular; e, extracellular.