Duo Jin

CD38 is critical for social behaviour by regulating oxytocin secretion

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.

Two genetic variants of CD38 in subjects with autism spectrum disorder and controls.

The neurobiological basis of autism spectrum disorder (ASD) remains poorly understood. Given the role of CD38 in social recognition through oxytocin (OT) release, we hypothesized that CD38 may play a role in the etiology of ASD. Here, we first examined the immunohistochemical expression of CD38 in the hypothalamus of post-mortem brains of non-ASD subjects and found that CD38 was colocalized with OT in secretory neurons. In studies of the association between CD38 and autism, we analyzed 10 single nucleotide polymorphisms (SNPs) and mutations of CD38 by re-sequencing DNAs mainly from a case-control study in Japan, and Caucasian cases mainly recruited to the Autism Genetic Resource Exchange (AGRE). The SNPs of CD38, rs6449197 (p<0.040) and rs3796863 (p<0.005) showed significant associations with a subset of ASD (IQ>70; designated as high-functioning autism (HFA)) in the U.S. 104 AGRE family trios, but not with Japanese 188 HFA subjects. A mutation that caused tryptophan to replace arginine at amino acid residue 140 (R140W; (rs1800561, 4693C>T)) was found in 0.6-4.6% of the Japanese population and was associated with ASD in the smaller case-control study. The SNP was clustered in pedigrees in which the fathers and brothers of T-allele-carrier probands had ASD or ASD traits. In this cohort OT plasma levels were lower in subjects with the T allele than in those without. One proband with the T allele who was taking nasal OT spray showed relief of symptoms. The two variant CD38 poloymorphysms tested may be of interest with regard of the pathophysiology of ASD.

Cyclic ADP-ribose as a universal calcium signal molecule in the nervous system

beta-NAD(+) is as abundant as ATP in neuronal cells. beta-NAD(+) functions not only as a coenzyme but also as a substrate. beta-NAD(+)-utilizing enzymes are involved in signal transduction. We focus on ADP-ribosyl cyclase/CD38 which synthesizes cyclic ADP-ribose (cADPR), a universal Ca(2+) mobilizer from intracellular stores, from beta-NAD(+). cADPR acts through activation/modulation of ryanodine receptor Ca(2+) releasing Ca(2+) channels. cADPR synthesis in neuronal cells is stimulated or modulated via different pathways and various factors. Subtype-specific coupling of various neurotransmitter receptors with ADP-ribosyl cyclase confirms the involvement of the enzyme in signal transduction in neurons and glial cells. Moreover, cADPR/CD38 is critical in oxytocin release from the hypothalamic cell dendrites and nerve terminals in the posterior pituitary. Therefore, it is possible that pharmacological manipulation of intracellular cADPR levels through ADP-ribosyl cyclase activity or synthetic cADPR analogues may provide new therapeutic opportunities for treatment of neurodevelopmental disorders.

Dopamine release via the vacuolar ATPase V0 sector c-subunit, confirmed in N18 neuroblastoma cells, results in behavioral recovery in hemiparkinsonian mice

A 16-kDa proteolipid, mediatophore, in Torpedo electric organs mediates Ca(2+)-dependent acetylcholine release. Mediatophore is identical to the pore-forming stalk c-subunit of the V0 sector of vacuolar proton ATPase (ATP6V0C). The function of ATP6V0C in the mammalian central nervous system is not clear. Here, we report transfection of adeno-associated viral vectors harboring rat ATP6V0C into the mouse substantia nigra, in which high potassium stimulation increased overflow of endogenous dopamine (DA) measured in the striatum by in vivo microdialysis. Next, in the striatum of 6-hydroxydopamine-lesioned mice, a model of Parkinsons disease (PD), human tyrosine hydroxylase, aromatic l-amino-acid decarboxylase and guanosine triphosphate cyclohydrolase 1, together with or without ATP6V0C, were expressed in the caudoputamen for rescue. Motor performance on the accelerating rotarod test and amphetamine-induced ipsilateral rotation were improved in the rescued mice coexpressing ATP6V0C. [(3)H]DA, taken up into cultured N18 neuronal tumor cells transformed to express ATP6V0C, was released by potassium stimulation. These results indicated that ATP6V0C mediates DA release from nerve terminals in the striatum of DA neurons of normal mice and from gene-transferred striatal cells of parkinsonian mice. The results suggested that ATP6V0C may be useful as a rescue molecule in addition to DA-synthetic enzymes in the gene therapy of PD.

Social Memory, Maternal Care, and Oxytocin Secretion, But not Vasopressin Release, Require CD38 In Mice

Publisher Summary The CD38-dependent cADPR or NAADP signaling pathway of Ca 2+ regulation has been demonstrated in cultured anterior pituitary tumor cells. This chapter describes effects of these pathways on posterior pituitary (neurohypophysial) hormone function in accordance with recent results. CD38 has been identified as a transmembrane receptor that triggers proliferation and immune responses in lymphocytes. CD38, thus, is frequently used as a malignancy or differentiation marker in chronic lymphocytic leukemia or HIV infection. CD38 is present in many tissues, such as the brain and pancreas. The intracellular Ca 2+ signaling mechanisms underlying oxytocin (OT) or arginine vasopressin (AVP) secretion are not fully understood and the mechanism for OT and AVP may not be the same. To address this issue, this discussion used CD38 gene knockout mice, and discovered that CD38-dependent cyclic ADP-ribose- and nicotinic acid adenine dinucleotide phosphate sensitive intracellular Ca 2+ mobilization plays a key role in OT release, but not AVP secretion, from soma and axon terminals of hypothalamic neurons, exerting profound actions on social behaviors. Alteration of CD38 function and the resultant disturbance of only OT secretion may be associated with some forms of impaired human behavior in the autism spectrum disorders.

Bradykinin activates ADP-ribosyl cyclase in neuroblastoma cells: intracellular concentration decrease in NAD and increase in cyclic ADP-ribose.

ADP‐ribosyl cyclase activity in the crude membrane fraction of neuroblastoma × glioma NGPM1‐27 hybrid cells was measured by monitoring [3H] cyclic ADP‐ribose (cADPR) formation from [3H] NAD+. Bradykinin (BK) at 100 nM increased ADP‐ribosyl cyclase activity by about 2.5‐fold. Application of 300 nM BK to living NGPM1‐27 cells decreased NAD+ to 78% of the prestimulation level at 30 s. In contrast, intracellular cADPR concentrations were increased by 2–3‐fold during the period from 30 to 120 s after the same treatment. Our results suggest that cADPR is one of the second messengers downstream of B2 BK receptors.

Lentiviral-vector-mediated gene rescue—Functional recovery by region-specific expression of CD38 gene

High-affinity choline transporter (CHT) is efficiently transported to cholinergic axon terminals. We have previously shown that most of the CHT is associated with synaptic vesicles rather than synaptic plasma membrane. Here, we analyzed intracellular distribution of CHT in adaptor protein-3 (AP-3) deficient mouse (mocha mouse). In the mouse, endosomal granular structures were intensely labeled with CHT antibody, indicating possible deficit in CHT trafficking. Western blot analysis revealed that CHT on synaptic vesicle in mocha mice was decreased by 70% compared with wild-type mice. However no significant difference in synaptosomal choline uptake activity was detected, implicating the existence of large pool for CHT. Furthermore most of CHT is found associated with synaptic-like micro-vesicles (SLMV) in CHT-overexpressed PC12 cells. The amounts of CHT detected on SLMV were greatly reduced by treating the cell with agents which halt AP-3, demonstrating AP-3 involvement in CHT trafficking.