Cyclic ADP-Ribose and NAADP: Structures, Metabolism and Functions
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White, et al. Author Index. Subject Index. Notes Includes bibliographical references and index. View online Borrow Buy Freely available Show 0 more links None of your libraries hold this item. Found at these bookshops Searching - please wait We were unable to find this edition in any bookshop we are able to search. These online bookshops told us they have this item:. Tags What are tags? Add a tag. Public Private login e.
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Add a tag Cancel Nicotinamide adenine dinucleotide. Lists What are lists? Login to add to list. By intercrossing, we produced NOD mice carrying the Reg transgene and found that the development of diabetes in the resultant Reg transgenic NOD mice was significantly retarded. We then produced Reg knockout mice by homologous recombination and found that the [ 3 H]thymidine incorporation in the islets was decreased.
The cDNA encoded a amino acid protein, and based on the amino acid sequence, the protein appears to be a type II transmembrane protein with a long extracellular domain. The binding of I-labeled rat Reg protein was displaced by increasing the concentration of unlabeled rat Reg protein. The receptor mRNA was expressed in normal pancreatic islets, regenerating islets, and a pancreatic ductal cell line ARIP cells, which proliferate in a Reg protein-dependent manner.
The Reg gene is only expressed during islet regeneration 60 , 66 , 67 , whereas there is no difference in the receptor mRNA expression between normal and regenerating islets The combined addition of IL-6 and dexamethasone increased the Reg mRNA level, and furthermore, addition of nicotinamide or 3-aminobenzamide increased the mRNA even more. The Reg and Reg -related genes were isolated and revealed to constitute a multigene family, the Reg gene family 66 , In humans, four REG family genes, i. In mouse genome, all of the Reg family genes, i. Type I and type II Reg proteins are expressed in regenerating islets Type III Reg proteins have been suggested to be involved in cellular proliferation in intestinal cells, hepatic cells, and neuronal cells.
Importantly, mouse Reg III was shown to be a Schwann cell mitogen that accompanies the regeneration of motor neurons 76 , and Reg protein functions as a neurotrophic factor for motor neurons Reg was also shown to mediate gastric mucosal proliferation in rats 78 , In fact, our preliminary histopathological analyses of Reg knockout mice showed that there are some structural abnormalities in tissue organization of alimentary tract and liver unpublished data.
Therefore, PARP inhibitors and their derivatives appear to be one of the most promising therapeutic approaches for diabetes treatment, although some toxic effects, such as reversible liver toxicity, teratogenicity, oncogenicity, and growth-retardation, were reported in animal models at very high doses of the inhibitor. However, it has been revealed that there is no evidence in humans of most of the toxic effects of nicotinamide that have been reported in animal models Complications of diabetes are very serious problems for patients in their quality of life.
As described in the text see Fig. The involvement of the CDcADPR signal system in these cells and tissues has also been described 5 — 8 , and the possible involvement of the Reg-Reg receptor system in Schwann cells, neuronal cells, and gastrointestinal cells has also been suggested 63 — Studies evaluating the incidence and severity of diabetic complications in the clinical PARP inhibitor trials will be required.
The Okamoto model for necrotic cell death. Under physiological conditions, apoptotic cell death constitutively occurs for renewal and maintenance in animal bodies, whereas necrotic cells initiate and enhance auto immune reactions under pathological conditions. The Okamoto model as the mechanism of necrotic cell death in many tissues and cells in various diseases B. Islets were isolated from fasted rats and incubated with Krebs-Ringer bicarbonate buffer containing 2.
The cADPR content was calculated by accounting for the recovery of cADPR in the extraction and concentration procedures and expressed as fentomoles per microgram of islet protein. Vertical bars indicate SE. HG, high glucose; LG, low glucose. Islets were perfused with Krebs-Ringer buffer containing 2. The interval between successive images of recordings was 4 s. G : Insulin secretion from isolated islets under various glucose concentrations. G3PDH, glyceraldehydephosphate dehydrogenase. Various physiological phenomena from animal to plant cells become understandable in terms of this novel signal system 6 — 8.
Once PARP is self-poly ADP-ribosyl ated, the formation of the Reg gene transcriptional complex is inhibited, interfering with the interaction between PARP and other nuclear proteins necessary for the active complex, and therefore the transcription of Reg gene stops. Alignment of amino acid sequences of the Reg gene family.
Cyclic ADP-Ribose and NAADP: Structures, Metabolism and Functions
Based on the primary structures of the encoded proteins adapted from 67 , and see also 74 and 75 , the members of the Reg gene family are grouped into four subclasses: type I, II, III, and IV. Dashes indicate gaps for maximal alignment. Arrowheads indicate six conserved cysteines in the mature proteins. Roles of PARP and its inhibitors for cell death, regeneration, and functioning adapted from 7. The symposium and the publication of this article have been made possible by an unrestricted educational grant from Servier, Paris.
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The Okamoto model in various diseases. Reg receptor. The Reg gene family in tissue regeneration.
We are grateful to Mr. Brent Bell for critical reading of the manuscript. Received for publication 15 March and accepted in revised form16 May Mol Cell Biochem 37 : 43 —61, Okamoto H: Molecular basis of experimental diabetes: degeneration, oncogenesis, and regeneration of pancreatic B-cells of islets of Langerhans. BioEssays 2 : 15 —21, London, John Libbey, , p. Okamoto H: The molecular basis of experimental diabetes.
In Molecular biology of the islets of Langerhans. Okamoto H, Ed. Cambridge, Cambridge University Press, , p. Diabetologia 40 : —, Chem Immunol 75 : —, Int J Exp Diabetes Res 3 : 79 —96, Lee HC, Ed. Dordrecht, the Netherlands, Kluwer. In press. Nature Med 5 : —, Nature : —, Volume Issue 6.
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J Biol Chem , —, ADP-ribosyl cyclases generate two unusual adenine homodinucleotides with cytotoxic activity on mammalian cells. The new life of a centenarian: signaling functions of NAD P. Trends in Biochem Sci 29 , —, Methods Enzymol 66 , —, Biochem J , —, Circ Res 91 , —, Nature , 74—76,