NMNAT1 is a nuclear protein with a predicted nuclear localization signal (NLS) between Glu107–Lys146 [87]. NMNAT2 is localized to the Golgi apparatus via palmitoylation of Cys164 and Cys165 [4, 87]. In the mouse brain, NMNAT2 is enriched in numerous membrane compartments, including synaptic terminals and synaptic vesicles [4, 22]. NMNAT3 is predominantly localized in mitochondria and its first 25 residues encode a mitochondrial targeting sequence [50]. NAD+, the enzymatic product of NMNATs, is an essential cofactor for many metabolic processes, transcriptional regulation and several protein modification reactions. The NAD signaling pathway generates precursors of several intracellular calcium mobilizing agents including cADPR and NAADP. Abbreviations: ADPR, ADP-ribose; CAC, citric acid cycle; cADPR, cyclic ADP-ribose; NAADP, nicotinic acid adenine dinucleotide phosphate; NADase, bifunctional NAD glycohydrolase/ADP-ribosylcyclase; PARP, poly-ADP-ribose polymerase.