scholarly journals CD38-dependent ADP-ribosyl cyclase activity in developing and adult mouse brain

2003 ◽  
Vol 370 (1) ◽  
pp. 175-183 ◽  
Author(s):  
Claire CENI ◽  
Nathalie POCHON ◽  
Virginie BRUN ◽  
Hélène MULLER-STEFFNER ◽  
Annie ANDRIEUX ◽  
...  
Keyword(s):  
Developmental Stages ◽  
The Body ◽  
Adult Brain ◽  
Cyclase Activity ◽  
Wild Type ◽  
Intracellular Location ◽  
Nad Glycohydrolase ◽  
Adp Ribosyl Cyclase ◽  
Activity Measurements ◽  
Cyclic Adp Ribose

CD38 is a transmembrane glycoprotein that is expressed in many tissues throughout the body. In addition to its major NAD+-glycohydrolase activity, CD38 is also able to synthesize cyclic ADP-ribose, an endogenous calcium-regulating molecule, from NAD+. In the present study, we have compared ADP-ribosyl cyclase and NAD+-glycohydrolase activities in protein extracts of brains from developing and adult wild-type and Cd38-/- mice. In extracts from wild-type brain, cyclase activity was detected spectrofluorimetrically, using nicotinamide—guanine dinucleotide as a substrate (GDP-ribosyl cyclase activity), as early as embryonic day 15. The level of cyclase activity was similar in the neonate brain (postnatal day 1) and then increased greatly in the adult brain. Using [14C]NAD+ as a substrate and HPLC analysis, we found that ADP-ribose is the major product formed in the brain at all developmental stages. Under the same experimental conditions, neither NAD+-glycohydrolase nor GDP-ribosyl cyclase activity could be detected in extracts of brains from developing or adult Cd38-/- mice, demonstrating that CD38 is the predominant constitutive enzyme endowed with these activities in brain at all developmental stages. The activity measurements correlated with the level of CD38 transcripts present in the brains of developing and adult wild-type mice. Using confocal microscopy we showed, in primary cultures of hippocampal cells, that CD38 is expressed by both neurons and glial cells, and is enriched in neuronal perikarya. Intracellular NAD+-glycohydrolase activity was measured in hippocampal cell cultures, and CD38-dependent cyclase activity was higher in brain fractions enriched in intracellular membranes. Taken together, these results lead us to speculate that CD38 might have an intracellular location in neural cells in addition to its plasma membrane location, and may play an important role in intracellular cyclic ADP-ribose-mediated calcium signalling in brain tissue.

scholarly journals Identification of bovine liver mitochondrial NAD+ glycohydrolase as ADP-ribosyl cyclase

1997 ◽  
Vol 326 (2) ◽  
pp. 401-405 ◽  
Author(s):  
Mathias ZIEGLER ◽  
Dierk JORCKE ◽  
Manfred SCHWEIGER
Keyword(s):  
Calcium Release ◽  
Bovine Liver ◽  
Enzymic Activity ◽  
Cyclase Activity ◽  
Partial Recovery ◽  
Nad Glycohydrolase ◽  
Adp Ribosyl Cyclase ◽  
Cyclic Adp Ribose ◽  
Hydrolysis Of ◽  
Synthesis And Degradation

The present investigation identifies bovine liver mitochondrial NADase (NAD+ glycohydrolase) as a member of the class of bifunctional ADP-ribosyl cyclases/cyclic ADP-ribose hydrolases, known to be potential second messenger enzymes. These enzymes catalyse the synthesis and degradation of cyclic ADP-ribose, a potent intracellular calcium-mobilizing agent. The mitochondrial enzyme utilized the NAD+ analogues nicotinamide guanine dinucleotide (NGD+) and nicotinamide hypoxanthine dinucleotide (NHD+) to form fluorescent cyclic purine nucleoside diphosphoriboses. ADP-ribosyl cyclase activity was also demonstrated using 32P-labelled NAD+ as substrate. The identity of NADase and ADP-ribosyl cyclase was supported by their co-migration in SDS/polyacrylamide gels. Cyclase activity was visualized directly within the gel by detecting the formation of fluorescent cyclic IDP-ribose from NHD+. The enzyme catalysed the hydrolysis of cyclic ADP-ribose to ADP-ribose. Moreover, in the presence of nicotinamide and cyclic ADP-ribose the enzyme synthesized NAD+. Both the ADP-ribosyl cyclase and NADase activities of the enzyme were strongly inhibited by reducing agents. Treatment of the NADase with dithiothreitol caused the apparent inactivation of the enzyme. Subsequent removal of the reducing agent and addition of oxidized glutathione led to a partial recovery of enzymic activity. The results support a model for pro-oxidant-induced calcium release from mitochondria involving cyclic ADP-ribose as a specific messenger, rather than the non-enzymic modification of proteins by ADP-ribose.

scholarly journals Snake venom NAD glycohydrolases: primary structures, genomic location, and gene structure

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e6154 ◽  
Author(s):  
Ivan Koludarov ◽  
Steven D. Aird
Keyword(s):  
Snake Venom ◽  
Active Site ◽  
Disulfide Bonds ◽  
Venom Gland ◽  
Catalytic Residue ◽  
Nad Glycohydrolase ◽  
Adp Ribosyl Cyclase ◽  
Genomic Location ◽  
Cyclic Adp Ribose ◽  
Very High

NAD glycohydrolase (EC 3.2.2.5) (NADase) sequences have been identified in 10 elapid and crotalid venom gland transcriptomes, eight of which are complete. These sequences show very high homology, but elapid and crotalid sequences also display consistent differences. As in Aplysia kurodai ADP-ribosyl cyclase and vertebrate CD38 genes, snake venom NADase genes comprise eight exons; however, in the Protobothrops mucrosquamatus genome, the sixth exon is sometimes not transcribed, yielding a shortened NADase mRNA that encodes all six disulfide bonds, but an active site that lacks the catalytic glutamate residue. The function of this shortened protein, if expressed, is unknown. While many vertebrate CD38s are multifunctional, liberating both ADP-ribose and small quantities of cyclic ADP-ribose (cADPR), snake venom CD38 homologs are dedicated NADases. They possess the invariant TLEDTL sequence (residues 144–149) that bounds the active site and the catalytic residue, Glu228. In addition, they possess a disulfide bond (Cys121–Cys202) that specifically prevents ADP-ribosyl cyclase activity in combination with Ile224, in lieu of phenylalanine, which is requisite for ADPR cyclases. In concert with venom phosphodiesterase and 5′-nucleotidase and their ecto-enzyme homologs in prey tissues, snake venom NADases comprise part of an envenomation strategy to liberate purine nucleosides, and particularly adenosine, in the prey, promoting prey immobilization via hypotension and paralysis.

scholarly journals Human CD38 is an authentic NAD(P)+ glycohydrolase

1998 ◽  
Vol 330 (3) ◽  
pp. 1383-1390 ◽  
Author(s):  
Valérie BERTHELIER ◽  
Jean-Michel TIXIER ◽  
Hélène MULLER-STEFFNER ◽  
Francis SCHUBER ◽  
Philippe DETERRE
Keyword(s):  
Molecular Mechanisms ◽  
Reaction Scheme ◽  
Reaction Pathways ◽  
Catalytic Activities ◽  
Nad Glycohydrolase ◽  
Cyclization Process ◽  
Adp Ribosyl Cyclase ◽  
Cyclic Adp Ribose ◽  
Water Hydrolysis ◽  
Low Efficiency

The leucoyte surface antigen CD38 has been shown to be an ecto-enzyme with multiple catalytic activities. It is principally a NAD+ glycohydrolase that transforms NAD+ into ADP-ribose and nicotinamide. CD38 is also able to produce small amounts of cyclic ADP-ribose (ADP-ribosyl cyclase activity) and to hydrolyse this cyclic metabolite into ADP-ribose (cyclic ADP-ribose hydrolase activity). To classify CD38 among the enzymes that transfer the ADP-ribosyl moiety of NAD+ to a variety of acceptors, we have investigated its substrate specificity and some characteristics of its kinetic and molecular mechanisms. We find that CD38-catalysed cleavage of the nicotinamide-ribose bond results in the formation of an E·ADP-ribosyl intermediary complex, which is common to all reaction pathways; this intermediate reacts (1) with acceptors such as water (hydrolysis), methanol (methanolysis) or pyridine (transglycosidation), and (2) intramolecularly, yielding cyclic ADP-ribose with a low efficiency. This reaction scheme is also followed when using nicotinamide guanine dinucleotide as an alternative substrate; in this case, however, the cyclization process is highly favoured. The results obtained here are not compatible with the prevailing model for the mode of action of CD38, according to which this enzyme produces first cyclic ADP-ribose which is then immediately hydrolysed into ADP-ribose (i.e. sequential ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase activities). We show instead that the cyclic metabolite was a reaction product of CD38 rather than an obligatory reaction intermediate during the glycohydrolase activity. Altogether our results lead to the conclusion that CD38 is an authentic ‘classical’ NAD(P)+ glycohydrolase (EC 3.2.2.6).

scholarly journals Renal vasoconstriction by vasopressin V1a receptors is modulated by nitric oxide, prostanoids, and superoxide but not the ADP ribosyl cyclase CD38

2014 ◽  
Vol 306 (10) ◽  
pp. F1143-F1154 ◽  
Author(s):  
Nicholas G. Moss ◽  
Tayler E. Kopple ◽  
William J. Arendshorst
Keyword(s):  
Nitric Oxide ◽  
Contractile Response ◽  
Receptor Activation ◽  
Wild Type ◽  
Renal Vasoconstriction ◽  
Adp Ribosyl Cyclase ◽  
Cyclic Adp Ribose ◽  
Renal Vascular ◽  
Dose Dependent

Renal blood flow (RBF) responses to arginine vasopressin (AVP) were tested in anesthetized wild-type (WT) and CD38−/− mice that lack the major calcium-mobilizing second messenger cyclic ADP ribose. AVP (3–25 ng) injected intravenously produced dose-dependent decreases in RBF, reaching a maximum of 25 ± 2% below basal RBF in WT and 27 ± 2% in CD38−/− mice with 25 ng of AVP. Renal vascular resistance (RVR) increased 75 ± 6% and 78 ± 6% in WT and CD38−/− mice. Inhibition of nitric oxide (NO) synthase with nitro-l-arginine methyl ester (l-NAME) increased the maximum RVR response to AVP to 308 ± 76% in WT and 388 ± 81% in CD38−/− ( P < 0.001 for both). Cyclooxygenase inhibition with indomethacin increased the maximum RVR response to 125 ± 15% in WT and 120 ± 14% in CD38−/− mice ( P < 0.001, <0.05). Superoxide suppression with tempol inhibited the maximum RVR response to AVP by 38% in both strains ( P < 0.005) but was ineffective when administered after l-NAME. The rate of RBF recovery (relaxation) after AVP was slowed by l-NAME and indomethacin ( P < 0.001, <0.005) but was unchanged by tempol. All vascular responses to AVP were abolished by an AVP V1a receptor antagonist. A V2 receptor agonist or antagonist had no effect on AVP-induced renal vasoconstriction. Taken together, the results indicate that renal vasoconstriction by AVP in the mouse is strongly buffered by vasodilatory actions of NO and prostanoids. The vasoconstriction depends on V1a receptor activation without involvement of CD38 or concomitant vasodilatation by V2 receptors. The role of superoxide is to enhance the contractile response to AVP, most likely by reducing the availability of NO rather than directly stimulating intracellular contraction signaling pathways.

scholarly journals Oscillation of ADP-ribosyl cyclase activity during the cell cycle and function of cyclic ADP-ribose in a unicellular organism, Euglena gracilis

FEBS Letters ◽  
1997 ◽  
Vol 405 (1) ◽  
pp. 104-106 ◽  
Author(s):  
Wataru Masuda ◽  
Shigeo Takenaka ◽  
Kiyoshi Inageda ◽  
Hiroshi Nishina ◽  
Katsunobu Takahashi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Euglena Gracilis ◽  
Cyclase Activity ◽  
Unicellular Organism ◽  
Adp Ribosyl Cyclase ◽  
Cyclic Adp Ribose ◽  
And Function

Catalytic properties of the retinal rod outer segment disk ADP-ribosyl cyclase

2011 ◽  
Vol 28 (2) ◽  
pp. 121-128 ◽  
Author(s):  
ANDREA FABIANO ◽  
ISABELLA PANFOLI ◽  
DANIELA CALZIA ◽  
MAURIZIO BRUSCHI ◽  
SILVIA RAVERA ◽  
...  
Keyword(s):  
Divalent Cations ◽  
Cyclase Activity ◽  
The Novel ◽  
Intracellular Membrane ◽  
Adp Ribosyl Cyclase ◽  
Retinal Rod ◽  
Cyclic Adp Ribose ◽  
Response To Change ◽  
Shed Light

AbstractCyclic ADP-ribose (cADPR) is a second messenger modulating intracellular calcium levels. We have previously described a cADPR-dependent calcium signaling pathway in bovine rod outer segments (ROS), where calcium ions play a pivotal role. ROS ADP-ribosyl cyclase (ADPR-cyclase) was localized in the membrane fraction. In the present work, we examined the properties of the disk ADPR-cyclase through the production of cyclic GDP-ribose from the NAD+ analogue NGD+. The enzyme displayed an estimated Km for NGD+ of 12.5 ± 0.3 μM, a Vmax of 26.50 ± 0.70 pmol cyclic GDP-ribose synthesized/min/mg, and optimal pH of 6.5. The effect of divalent cations (Zn2+, Cu2+, and Ca2+) was also tested. Micromolar Zn2+ and Cu2+ inhibited the disk ADPR-cyclase activity (half maximal inhibitory concentration, IC50 = 1.1 and 3.6 μM, respectively). By contrast, Ca2+ ions had no effect. Interestingly, the properties of the intracellular membrane–associated ROS disk ADPR-cyclase are more similar to those of the ADPR-cyclase found in CD38-deficient mouse brain, than to those of CD38 or CD157. The novel intracellular mammalian ADPR-cyclase would elicit Ca2+ release from the disks at various rates in response to change in free Ca2+ concentrations, caused by light versus dark adaptation, in fact there was no difference in disk ADPR-cyclase activity in light or dark conditions. Data suggest that disk ADPR-cyclase may be a potential target of retinal toxicity of Zn2+ and may shed light to the role of Cu2+ and Zn2+ deficiency in retina.

scholarly journals Angiotensin II stimulates cyclic ADP-ribose formation in neonatal rat cardiac myocytes

2000 ◽  
Vol 352 (1) ◽  
pp. 197-202 ◽  
Author(s):  
Haruhiro HIGASHIDA ◽  
Jia-Sheng ZHANG ◽  
Minako HASHII ◽  
Miyuki SHINTAKU ◽  
Chiharu HIGASHIDA ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Ventricular Myocytes ◽  
Receptor Activation ◽  
Neonatal Rat ◽  
Cyclase Activity ◽  
Ventricular Muscle ◽  
Ang Ii ◽  
Adult Rats ◽  
Adp Ribosyl Cyclase ◽  
Cyclic Adp Ribose

To examine the role of cyclic ADP-ribose (cADP-ribose) as a second messenger downstream of angiotensin II (Ang II) receptor activation in the heart, ADP-ribosyl cyclase activity was measured in a crude membrane fraction of ventricular myocytes. Ang II at 10–100nM increased ADP-ribosyl cyclase activity by 40–90% in the ventricular muscle of neonatal (2–4-day-old) rats, but not in fetal or adult hearts. This increase was inhibited by the Ang II antipeptide. Stimulation of ADP-ribosyl cyclase was reproduced by GTP and guanosine 5´-[γ-thio]triphosphate, and prevented by guanosine 5´-[β-thio]diphosphate. Prior treatment of the rats with cholera toxin A and B subunits also blocked the Ang II-induced activation. The density of Ang II receptors detected as [3H]Ang II binding was higher in neonatal than adult rats. These results demonstrate the existence of a signalling pathway from Ang II receptors to membrane-bound ADP-ribosyl cyclase in the ventricular muscle cell and suggest that the Ang II-induced increase in cADP-ribose synthesis is involved in the regulation of cardiac function and development.

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