CD38 is the major enzyme responsible for synthesis of nicotinic acid–adenine dinucleotide phosphate in mammalian tissues

2002 ◽  
Vol 362 (1) ◽  
pp. 125-130 ◽  
Author(s):  
Eduardo N. CHINI ◽  
Claudia C. S. CHINI ◽  
Ichiro KATO ◽  
Shin TAKASAWA ◽  
Hiroshi OKAMOTO
Keyword(s):  
Nicotinic Acid ◽  
Knockout Mice ◽  
Second Messenger ◽  
Signalling Pathway ◽  
Rat Tissues ◽  
Mammalian Tissues ◽  
Cyclic Adp Ribose

In the present study, we have determined the role of the enzyme CD38 upon the synthesis of the Ca2+-releasing nucleotide nicotinic acid—adenine dinucleotide phosphate (NAADP). In rat tissues, we observed that the capacity for NAADP synthesis could be co-immunoprecipitated with CD38 using an anti-CD38 antibody. Furthermore, we observed that several tissues from CD38 knockout mice had no capacity for the synthesis of this nucleotide. In addition, CD38 was also identified as the major enzyme responsible for the synthesis of the second messenger cyclic ADP-ribose. These observations lead to the conclusion that CD38 is the major enzyme responsible for the synthesis of NAADP and cyclic ADP-ribose, and raises the possibility of a new signalling pathway where two different Ca2+-releasing nucleotides are synthesized by the same enzyme.

Role of cyclic ADP-ribose in the regulation of [Ca2+]i in porcine tracheal smooth muscle

1998 ◽  
Vol 274 (6) ◽  
pp. C1653-C1660 ◽  
Author(s):  
Y. S. Prakash ◽  
Mathur S. Kannan ◽  
Timothy F. Walseth ◽  
Gary C. Sieck
Keyword(s):  
Smooth Muscle ◽  
Second Messenger ◽  
Ruthenium Red ◽  
Tracheal Smooth Muscle ◽  
Cyclic Adp Ribose ◽  
Intracellular Ca ◽  
Subsequent Exposure ◽  
Trisphosphate Receptor ◽  
Dose Dependent Increase

The purpose of the present study was to determine whether cyclic ADP-ribose (cADPR) acts as a second messenger for Ca2+ release through ryanodine receptor (RyR) channels in tracheal smooth muscle (TSM). Freshly dissociated porcine TSM cells were permeabilized with β-escin, and real-time confocal microscopy was used to examine changes in intracellular Ca2+ concentration ([Ca2+]i). cADPR (10 nM–10 μM) induced a dose-dependent increase in [Ca2+]i, which was blocked by the cADPR receptor antagonist 8-amino-cADPR (20 μM) and by the RyR blockers ruthenium red (10 μM) and ryanodine (10 μM), but not by the inositol 1,4,5-trisphosphate receptor blocker heparin (0.5 mg/ml). During steady-state [Ca2+]ioscillations induced by acetylcholine (ACh), addition of 100 nM and 1 μM cADPR increased oscillation frequency and decreased peak-to-trough amplitude. ACh-induced [Ca2+]ioscillations were blocked by 8-amino-cADPR; however, 8-amino-cADPR did not block the [Ca2+]iresponse to a subsequent exposure to caffeine. These results indicate that cADPR acts as a second messenger for Ca2+ release through RyR channels in TSM cells and may be necessary for initiating ACh-induced [Ca2+]ioscillations.

scholarly journals Polyamine homeostasis in arginase knockout mice

2007 ◽  
Vol 293 (4) ◽  
pp. C1296-C1301 ◽  
Author(s):  
Joshua L. Deignan ◽  
Justin C. Livesay ◽  
Lisa M. Shantz ◽  
Anthony E. Pegg ◽  
William E. O'Brien ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Polyamine Metabolism ◽  
Mrna Levels ◽  
Ornithine Aminotransferase ◽  
Double Knockout ◽  
Mammalian Tissues ◽  
Knockout Animals ◽  
Regulatory Functions ◽  
Arginase I

The role of ornithine decarboxylase (ODC) in polyamine metabolism has long been established, but the exact source of ornithine has always been unclear. The arginase enzymes are capable of producing ornithine for the production of polyamines and may hold important regulatory functions in the maintenance of this pathway. Utilizing our unique set of arginase single and double knockout mice, we analyzed polyamine levels in the livers, brains, kidneys, and small intestines of the mice at 2 wk of age, the latest timepoint at which all of them are still alive, to determine whether tissue polyamine levels were altered in response to a disruption of arginase I (AI) and II (AII) enzymatic activity. Whereas putrescine was minimally increased in the liver and kidneys from the AII knockout mice, spermidine and spermine were maintained. ODC activity was not greatly altered in the knockout animals and did not correlate with the fluctuations in putrescine. mRNA levels of ornithine aminotransferase (OAT), antizyme 1 (AZ1), and spermidine/spermine- N1-acetyltransferase (SSAT) were also measured and only minor alterations were seen, most notably an increase in OAT expression seen in the liver of AI knockout and double knockout mice. It appears that putrescine catabolism may be affected in the liver when AI is disrupted and ornithine levels are highly reduced. These results suggest that endogenous arginase-derived ornithine may not directly contribute to polyamine homeostasis in mice. Alternate sources such as diet may provide sufficient polyamines for maintenance in mammalian tissues.

scholarly journals Cyclic ADP-ribose is a second messenger in the lipopolysaccharide-stimulated proliferation of human peripheral blood mononuclear cells

2003 ◽  
Vol 375 (2) ◽  
pp. 395-403 ◽  
Author(s):  
Santina BRUZZONE ◽  
Antonio DE FLORA ◽  
Cesare USAI ◽  
Richard GRAEFF ◽  
Hon Cheung LEE
Keyword(s):  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Second Messenger ◽  
Immune Recognition ◽  
Adp Ribosyl Cyclase ◽  
T Lymphocyte Proliferation ◽  
Cyclic Adp Ribose ◽  
Membrane Bound

Cyclic ADP-ribose (cADPR), a universal calcium mobilizer from intracellular stores, was recently demonstrated to stimulate proliferation of various cell types. The role of cADPR in a specific process of monocyte- and plasma-mediated activation of T-lymphocytes by lipopolysaccharide (LPS) was addressed using human mononuclear cells from peripheral blood (PBMCs). Incubation of PBMCs with 0.1 μg/ml of LPS for 24 h provided a doubling in the intracellular levels of cADPR as compared with unstimulated PBMCs. The cADPR increase was abolished either by prior removal of monocytes or by pre-incubating a whole PBMC population with a monoclonal antibody against the monocyte marker CD14. The increased concentrations of intracellular cADPR elicited by LPS stimulation were paralleled by significant increases in NAD+ levels and in the activities of ectocellular and membrane-bound fractions of ADP-ribosyl cyclase/cADPR hydrolase activities. A cytosolic ADP-ribosyl cyclase was also detectable in PBMCs and its activity was comparably enhanced by LPS stimulation. This soluble cyclase is distinguished from the membrane-bound cyclase by both substrate and inhibitor sensitivities. LPS-stimulated PBMCs showed 2–3-fold increases of intracellular calcium ([Ca2+]i), and these changes were prevented completely by the cADPR antagonist 8-Br-cADPR and by ryanodine. Both compounds, and the cyclase inhibitor nicotinamide, significantly inhibited the T-lymphocyte proliferation induced by LPS in PBMCs. These results demonstrate that cADPR plays a role of second messenger in the adaptive immune recognition process of LPS-stimulated proliferation of PBMCs.

scholarly journals Role of the Second-Messenger Cyclic-Adenosine 5′-Diphosphate-Ribose on Adrenocorticotropin Secretion from Pituitary Cells

Endocrinology ◽  
2005 ◽  
Vol 146 (5) ◽  
pp. 2186-2192 ◽  
Author(s):  
Sandra M. Soares ◽  
Michael Thompson ◽  
Eduardo N. Chini
Keyword(s):  
Tumor Cell ◽  
Receptor Antagonist ◽  
Ryanodine Receptor ◽  
Tumor Cell Line ◽  
Second Messenger ◽  
Pituitary Cells ◽  
Acth Secretion ◽  
Cyclic Adp Ribose ◽  
Ryanodine Channel

Abstract We examined the role of the second-messenger cyclic-ADP-ribose (cADPR) on the regulation of ACTH secretion using AtT20 corticotroph tumor cell line. We found that the cADPR antagonist, 8-Br-cADPR, substantially diminished the secretion of ACTH induced by CRH and potassium in these cells, whereas xestospongin C, an inositol 1,4,5-triphosphate receptor antagonist, had no effect. In addition, the cADPR agonist, 3-deaza-cADPR, augmented ACTH secretion. The presence of the components of the cADPR system, namely ryanodine receptor, CD38, and cADPR itself, was determined in AtT20 cells. Furthermore, we observed that antagonists of the ryanodine channel and cADPR system can decrease the potassium-induced Ca2+ transients in these cells. These results suggest that cADPR is a second messenger in pituitary cells and regulates ACTH secretion by a mechanism dependent on activation of the ryanodine channel by extracellular Ca2+.

Nicotinic acid adenine dinucleotide phosphate: a new intracellular second messenger?

2002 ◽  
Vol 282 (6) ◽  
pp. C1191-C1198 ◽  
Author(s):  
Eduardo N. Chini ◽  
Frederico G. S. De Toledo
Keyword(s):  
T Cell ◽  
Nicotinic Acid ◽  
T Cell Activation ◽  
Pancreatic Secretion ◽  
Cell Activation ◽  
Second Messenger ◽  
Unanswered Question ◽  
Physiological Processes ◽  
Intracellular Ca

Nicotinic acid adenine dinucleotide phosphate (NAADP) is one of the most potent stimulators of intracellular Ca2+ release known to date. The role of the NAADP system in physiological processes is being extensively investigated at the present time. Exciting new discoveries in the last 5 years suggest that the NAADP-regulated system may have a significant role in intracellular Ca2+ signaling. The NAADP receptor and its associated Ca2+ pool have been hypothesized to be important in several physiological processes including fertilization, T cell activation, and pancreatic secretion. However, whether NAADP is a new second messenger or a tool for the discovery of a new Ca2+ channel is still an unanswered question.

Role of Ins(1,4,5)P3, cADP-ribose and nicotinic acid–adenine dinucleotide phosphate in Ca2+ signalling in mouse submandibular acinar cells

2001 ◽  
Vol 353 (3) ◽  
pp. 555-560 ◽  
Author(s):  
Alexander R. HARMER ◽  
David V. GALLACHER ◽  
Peter M. SMITH
Keyword(s):  
Nicotinic Acid ◽  
Second Messengers ◽  
Full Range ◽  
Acinar Cells ◽  
Second Messenger ◽  
Pancreatic Acinar Cells ◽  
Current Response ◽  
Transient Activation ◽  
High Concentrations

cADP-ribose (cADPr) and nicotinic acid–adenine dinucleotide phosphate (NAADP) are two putative second messengers; they were first shown to stimulate Ca2+ mobilization in sea urchin eggs. We have used the patch-clamp whole-cell technique to determine the role of cADPr and NAADP in relation to that of Ins(1,4,5)P3 in mouse submandibular acinar cells by measuring agonist-evoked and second-messenger-evoked changes in Ca2+-dependent K+ and Cl- currents. Both Ins(1,4,5)P3 and cADPr were capable of reproducing the full range of responses normally seen in response to stimulation with acetylcholine (ACh). Low concentrations of agonist (10–20nM ACh) or second messenger [1–10µM Ins(1,4,5)P3 or cADPr] elicited a sporadic transient activation of the Ca2+-dependent currents; mid-range concentrations [50–500nM ACh, 50µM Ins(1,4,5)P3 or 50–100µM cADPr] elicited high-frequency (approx. 2Hz) trains of current spikes; and high concentrations [more than 500nM ACh, more than 50µM Ins(1,4,5)P3 or more than 100µM cADPr] gave rise to a sustained current response. The response to ACh was inhibited by antagonists of both the Ins(1,4,5)P3 receptor [Ins(1,4,5)P3R] and the ryanodine receptor (RyR) but could be completely blocked only by an Ins(1,4,5)P3R antagonist (heparin). NAADP (50nM to 100µM) did not itself activate the Ca2+-dependent ion currents, nor did it inhibit the activation of these currents by ACh. These results show that, in these cells, both Ins(1,4,5)P3R and RyR are involved in the propagation of the Ca2+ signal stimulated by ACh and that cADPr can function as an endogenous regulator of RyR. Furthermore, although NAADP might have a role in hormone-stimulated secretion in pancreatic acinar cells, it does not contribute to ACh-evoked secretion in submandibular acinar cells.

scholarly journals Role of the IL33 and IL1RL1 pathway in the pathogenesis of Immunoglobulin A vasculitis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Diana Prieto-Peña ◽  
Sara Remuzgo-Martínez ◽  
Fernanda Genre ◽  
Verónica Pulito-Cueto ◽  
Belén Atienza-Mateo ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Disease Onset ◽  
Immunoglobulin A ◽  
Genetic Network ◽  
Signalling Pathway ◽  
Immune Mediated ◽  
Increased Risk ◽  
Genotype And Allele Frequencies ◽  
Immunoglobulin A Vasculitis

AbstractCytokines signalling pathway genes are crucial factors of the genetic network underlying the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory vascular condition. An influence of the interleukin (IL)33- IL1 receptor like (IL1RL)1 signalling pathway on the increased risk of several immune-mediated diseases has been described. Accordingly, we assessed whether the IL33-IL1RL1 pathway represents a novel genetic risk factor for IgAV. Three tag polymorphisms within IL33 (rs3939286, rs7025417 and rs7044343) and three within IL1RL1 (rs2310173, rs13015714 and rs2058660), that also were previously associated with several inflammatory diseases, were genotyped in 380 Caucasian IgAV patients and 845 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when IL33 and IL1RL1 variants were analysed independently. Likewise, no statistically significant differences were found in IL33 or IL1RL1 genotype and allele frequencies when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when IL33 and IL1RL1 haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the clinical characteristics mentioned above. Our results suggest that the IL33-IL1RL1 signalling pathway does not contribute to the genetic network underlying IgAV.

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