3.2.2.6 evolution the CD38-cADPR signaling system is conserved during vertebrate evolution, phylogenetic tree 732501 3.2.2.6 malfunction ablation of the CD38 gene in mice causes multiple physiological defects, including impaired oxytocin release, that result in altered social behavior 731296 3.2.2.6 malfunction CD38 knockout mice manifest multiple defects relating to Ca2+ signaling, including that of insulin secretion, hormonal signaling in pancreatic acinar cells, migration of dendritic cell precursors, bone resorption, airway responsiveness, alpha-adrenoceptor signaling in aorta, cardiac hypertrophy, susceptibility to bacterial infection, as well as social behavior in mice through modulation of oxytocin secretion 716910 3.2.2.6 malfunction CD38 reductions lead to microglial apoptosis. inhibition of CD38/cADPR-dependent signaling by CD38 silencing or 8-bromo-cADPR, a ryanodine receptor antagonist, produced significant ATP release from BV2 microglia. Cx43 small interfering RNA and Cx43 hemichannel blocker 18-alpha-glycyrrhetinic acid completely prevented the CD38 silencing or 8-bromo-cADPR-induced ATP release. Prevention of the ATP release might also be due to P2X7 receptor antagonists. Key role of ATP release in the microglial apoptosis induced by decreased CD38/cADPR-dependent signaling, overview 731882 3.2.2.6 additional information D226/Q226 and K129 residues of the two CD38 enzyme are the ADP-ribosylation sites. 6-Alkyne-F-araNAD, 6-alkyne-NAD, and Rh-N3 are used in the labeling reactions of CD38 wild-type and mutants, overview 731119 3.2.2.6 additional information invariant glutamate 218 identified is the catalytic residue of the enzyme, Structure homology modelling, overview 732691 3.2.2.6 additional information structure-function analysis, overview. The enzyme catalyzes the formation of beta-1'-O-methyl ADP-ribose in presence of methanol, solvolysis does not affect the overall turnover rate of NAD+ by the wild-type enzyme. Precise role of key conserved active site residues Trp118, Glu138, Asp147, Trp181 and Glu218, effects of experiments with neutral (methanol) and ionic (azide, formate) nucleophiles. Binding of 2'-fluorinated analogs of NAD+ and trappping of the reaction intermediate, detailed overview. Catalytic residue Glu138 is part of the TLEDTL signature domain, Asp147 is a highly conserved residue in the enzyme and is important for the catalytic parameters. Cooperative contribution of Trp118 and Trp181 to catalysis 731357 3.2.2.6 additional information structure-function relationship anaysis, overview. Covalent intermediates are formed with the catalytic residue, Glu226 731296 3.2.2.6 physiological function CD38 is an ectoenzyme that consumes NAD+ to produce cyclic ADP-ribose, a potent agonist of ryanodine receptors. Basal CD38/cyclic ADP-ribose-dependent signaling plays a key role in ATP release, which mediates basal survival of microglia, overview 731882 3.2.2.6 physiological function CD38 is an NAD+-metabolizing enzyme in mammals, a type II transmembrane protein that converts NAD+ primarily to adenosine diphosphate ribose and a small amount of cyclic adenosine diphosphate ribose. The major enzymatic function of the enzyme is to hydrolyze extracellular rather than intracellular NAD+ 731987