CD38, a transmembrane glycoprotein with ADP-ribosyl cyclase activity, catalyses the formation of Ca2+ signalling molecules, but its role in the neuroendocrine system is unknown. Here we show that adult CD38 knockout (CD38-/-) female and male mice show marked defects in maternal nurturing and social behaviour, respectively, with higher locomotor activity. Consistently, the plasma level of oxytocin (OT), but not vasopressin, was strongly decreased in CD38-/- mice. Replacement of OT by subcutaneous injection or lentiviral-vector-mediated delivery of human CD38 in the hypothalamus rescued social memory and maternal care in CD38-/- mice. Depolarization-induced OT secretion and Ca2+ elevation in oxytocinergic neurohypophysial axon terminals were disrupted in CD38-/- mice; this was mimicked by CD38 metabolite antagonists in CD38+/+ mice. These results reveal that CD38 has a key role in neuropeptide release, thereby critically regulating maternal and social behaviours, and may be an element in neurodevelopmental disorders.

Increases in [Ca 2؉] i in pancreatic beta cells, resulting from Ca 2؉ mobilization from intracellular stores as well as Ca 2؉ influx from extracellular sources, are important in insulin secretion by glucose. Cyclic ADP-ribose (cADPR), accumulated in beta cells by glucose stimulation, has been postulated to serve as a second messenger for intracellular Ca 2؉ mobilization for insulin secretion, and CD38 is thought to be involved in the cADPR accumulation (Takasawa, S., Tohgo, A., Noguchi, N., Koguma, T., Nata, K., Sugimoto, T., Yonekura, H., and Okamoto, H. (1993) J. Biol. Chem. 268, 26052-26054). Here we created "knockout" (CD38 ؊/؊ ) mice by homologous recombination. CD38؊/؊ mice developed normally but showed no increase in their glucose-induced production of cADPR in pancreatic islets. The glucose-induced [Ca 2؉ ] i rise and insulin secretion were both severely impaired in CD38 ؊/؊ islets, whereas CD38 ؊/؊ islets responded normally to the extracellular Ca 2؉ influx stimulants tolbutamide and KCl. CD38 ؊/؊ mice showed impaired glucose tolerance, and the serum insulin level was lower than control, and these impaired phenotypes were rescued by beta cell-specific expression of CD38 cDNA. These results indicate that CD38 plays an essential role in intracellular Ca 2؉ mobilization by cADPR for insulin secretion.Glucose stimulates insulin secretion in pancreatic beta cells of the islets of Langerhans, and mobilization of Ca 2ϩ from intracellular stores in the endoplasmic reticulum as well as Ca 2ϩ influx from extracellular sources has an important role in this process (1-3). Concerning the mechanism of Ca 2ϩ influx from extracellular sources, it has been thought that ATP generated in the process of glucose metabolism inhibits the ATPsensitive K ϩ channel, causing beta cell membrane depolarization, thereby opening the voltage-dependent Ca 2ϩ channel and resulting in Ca 2ϩ -influx from the extracellular space (4). On the other hand, we have recently proposed another pathway for the increase in the intracellular Ca 2ϩ concentration for insulin secretion by glucose via the CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose (cADPR) 1 hydrolase)-cADPR signal system in pancreatic beta cells (5-8): millimolar concentrations of ATP generated in the process of glucose metabolism induce cADPR accumulation by inhibiting the cADPR hydrolase activity of CD38 (9 -12), and cADPR then acts as a second messenger for intracellular Ca 2ϩ mobilization from the endoplasmic reticulum for insulin secretion (5,13,14).In the present study, we produced knockout mice carrying a null mutation in the CD38 gene by homologous recombination and found that CD38 disruption impairs glucose-induced increases in cADPR, intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ), and insulin secretion. EXPERIMENTAL PROCEDURESConstruction of the Targeting Vector-A 15-kbp mouse genomic DNA (BamHI-BamHI) fragment containing the first exon of the CD38 gene (DDBJ/EBI/GenBank TM accession number AB016868) was cloned from a TT2 embryonic stem (ES) cell (15) genomic library. The l...

An abnormal Ca(2+) leak through the RyR is present in heart failure, and this leak is presumably caused by a partial loss of RyR-bound FKBP12.6 and the resultant conformational change in RyR. This abnormal Ca(2+) leak might possibly cause Ca(2+) overload and consequent diastolic dysfunction, as well as systolic dysfunction.

Cyclic ADP-ribose (cADPR) is a second messenger for Ca 2؉ mobilization via the ryanodine receptor (RyR) from islet microsomes for insulin secretion (Takasawa, S., Nata, K., Yonekura, H., and Okamoto, H. (1993) Science 259, 370 -373). In the present study, FK506, an immunosuppressant that prolongs allograft survival, as well as cADPR were found to induce the release of Ca 2؉ from islet microsomes. After islet microsomes were treated with FK506, the Ca 2؉ release by cADPR from microsomes was reduced. cADPR as well as FK506 bound to FK506-binding protein 12.6 (FKBP12.6), which we also found occurs naturally in islet microsomes. When islet microsomes were treated with cADPR, FKBP12.6 dissociated from the microsomes and moved to the supernatant, releasing Ca 2؉ from the intracellular stores. The microsomes that were then devoid of FKBP12.6 did not show Ca 2؉ release by cADPR. These results strongly suggest that cADPR may be the ligand for FKBP12.6 in islet RyR and that the binding of cADPR to FKBP12.6 frees the RyR from FKBP12.6, causing it to release Ca 2؉ .