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1
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Guse AH. Enzymology of Ca 2+-Mobilizing Second Messengers Derived from NAD: From NAD Glycohydrolases to (Dual) NADPH Oxidases. Cells 2023; 12:cells12040675. [PMID: 36831342 PMCID: PMC9954121 DOI: 10.3390/cells12040675] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/14/2023] [Accepted: 02/16/2023] [Indexed: 02/23/2023] Open
Abstract
Nicotinamide adenine dinucleotide (NAD) and its 2'-phosphorylated cousin NADP are precursors for the enzymatic formation of the Ca2+-mobilizing second messengers adenosine diphosphoribose (ADPR), 2'-deoxy-ADPR, cyclic ADPR, and nicotinic acid adenine dinucleotide phosphate (NAADP). The enzymes involved are either NAD glycohydrolases CD38 or sterile alpha toll/interleukin receptor motif containing-1 (SARM1), or (dual) NADPH oxidases (NOX/DUOX). Enzymatic function(s) are reviewed and physiological role(s) in selected cell systems are discussed.
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Affiliation(s)
- Andreas H Guse
- The Calcium Signalling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
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2
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Paracrine ADP Ribosyl Cyclase-Mediated Regulation of Biological Processes. Cells 2022; 11:cells11172637. [PMID: 36078044 PMCID: PMC9454491 DOI: 10.3390/cells11172637] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/12/2022] [Accepted: 08/16/2022] [Indexed: 11/16/2022] Open
Abstract
ADP-ribosyl cyclases (ADPRCs) catalyze the synthesis of the Ca2+-active second messengers Cyclic ADP-ribose (cADPR) and ADP-ribose (ADPR) from NAD+ as well as nicotinic acid adenine dinucleotide phosphate (NAADP+) from NADP+. The best characterized ADPRC in mammals is CD38, a single-pass transmembrane protein with two opposite membrane orientations. The first identified form, type II CD38, is a glycosylated ectoenzyme, while type III CD38 has its active site in the cytosol. The ectoenzymatic nature of type II CD38 raised long ago the question of a topological paradox concerning the access of the intracellular NAD+ substrate to the extracellular active site and of extracellular cADPR product to its intracellular receptors, ryanodine (RyR) channels. Two different transporters, equilibrative connexin 43 (Cx43) hemichannels for NAD+ and concentrative nucleoside transporters (CNTs) for cADPR, proved to mediate cell-autonomous trafficking of both nucleotides. Here, we discussed how type II CD38, Cx43 and CNTs also play a role in mediating several paracrine processes where an ADPRC+ cell supplies a neighboring CNT-and RyR-expressing cell with cADPR. Recently, type II CD38 was shown to start an ectoenzymatic sequence of reactions from NAD+/ADPR to the strong immunosuppressant adenosine; this paracrine effect represents a major mechanism of acquired resistance of several tumors to immune checkpoint therapy.
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3
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Roles of cADPR and NAADP in pancreatic beta cell signalling. Cell Calcium 2022; 103:102562. [DOI: 10.1016/j.ceca.2022.102562] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 02/05/2022] [Accepted: 02/09/2022] [Indexed: 11/19/2022]
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4
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Lee HC, Zhao YJ. Resolving the topological enigma in Ca 2+ signaling by cyclic ADP-ribose and NAADP. J Biol Chem 2019; 294:19831-19843. [PMID: 31672920 PMCID: PMC6937575 DOI: 10.1074/jbc.rev119.009635] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) are two structurally distinct messengers that mobilize the endoplasmic and endolysosomal Ca2+ stores, respectively. Both are synthesized by the CD38 molecule (CD38), which has long been thought to be a type II membrane protein whose catalytic domain, intriguingly, faces to the outside of the cell. Accordingly, for more than 20 years, it has remained unresolved how CD38 can use cytosolic substrates such as NAD and NADP to produce messengers that target intracellular Ca2+ stores. The discovery of type III CD38, whose catalytic domain faces the cytosol, has now begun to clarify this topological conundrum. This article reviews the ideas and clues leading to the discovery of the type III CD38; highlights an innovative approach for uncovering its natural existence; and discusses the regulators of its activity, folding, and degradation. We also review the compartmentalization of cADPR and NAADP biogenesis. We further discuss the possible mechanisms that promote type III CD38 expression and appraise a proposal of a Ca2+-signaling mechanism based on substrate limitation and product translocation. The surprising finding of another enzyme that produces cADPR and NAADP, sterile α and TIR motif-containing 1 (SARM1), is described. SARM1 regulates axonal degeneration and has no sequence similarity with CD38 but can catalyze the same set of multireactions and has the same cytosolic orientation as the type III CD38. The intriguing finding that SARM1 is activated by nicotinamide mononucleotide to produce cADPR and NAADP suggests that it may function as a regulated Ca2+-signaling enzyme like CD38.
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Affiliation(s)
- Hon Cheung Lee
- State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China, 518055
| | - Yong Juan Zhao
- State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China, 518055
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5
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Horenstein AL, Bracci C, Morandi F, Malavasi F. CD38 in Adenosinergic Pathways and Metabolic Re-programming in Human Multiple Myeloma Cells: In-tandem Insights From Basic Science to Therapy. Front Immunol 2019; 10:760. [PMID: 31068926 PMCID: PMC6491463 DOI: 10.3389/fimmu.2019.00760] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 03/21/2019] [Indexed: 01/10/2023] Open
Abstract
Tumor microenvironments are rich in extracellular nucleotides that can be metabolized by ectoenzymes to produce adenosine, a nucleoside involved in controlling immune responses. Multiple myeloma, a plasma cell malignancy developed within a bone marrow niche, exploits adenosinergic pathways to customize the immune homeostasis of the tumor. CD38, a multifunctional protein that acts as both receptor and ectoenzyme, is overexpressed at all stages of myeloma. At neutral and acidic pH, CD38 catalyzes the extracellular conversion of NAD+ to regulators of calcium signaling. The initial disassembly of NAD+ is also followed by adenosinergic activity, if CD38 is operating in the presence of CD203a and CD73 nucleotidases. cAMP extruded from tumor cells provides another substrate for metabolizing nucleotidases to signaling adenosine. These pathways flank or bypass the canonical adenosinergic pathway subjected to the conversion of ATP by CD39. All of the adenosinergic networks can be hijacked by the tumor, thus controlling the homeostatic reprogramming of the myeloma in the bone marrow. In this context, adenosine assumes the role of a local hormone: cell metabolism is adjusted via low- or high-affinity purinergic receptors expressed by immune and bone cells as well as by tumor cells. The result is immunosuppression, which contributes to the failure of immune surveillance in cancer. A similar metabolic strategy silences immune effectors during the progression of indolent gammopathies to symptomatic overt multiple myeloma disease. Plasma from myeloma aspirates contains elevated levels of adenosine resulting from interactions between myeloma and other cells lining the niche and adenosine concentrations are known to increase as the disease progresses. This is statistically reflected in the International Staging System for multiple myeloma. Along with the ability to deplete CD38+ malignant plasma cell populations which has led to their widespread therapeutic use, anti-CD38 antibodies are involved in the polarization and release of microvesicles characterized by the expression of multiple adenosine-producing molecules. These adenosinergic pathways provide new immune checkpoints for improving immunotherapy protocols by helping to restore the depressed immune response.
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Affiliation(s)
- Alberto L Horenstein
- Laboratory of Immunogenetics, Department of Medical Sciences, Turin, Italy.,CeRMS, University of Torino, Turin, Italy
| | - Cristiano Bracci
- Laboratory of Immunogenetics, Department of Medical Sciences, Turin, Italy.,CeRMS, University of Torino, Turin, Italy
| | - Fabio Morandi
- Stem Cell Laboratory and Cell Therapy Center, Istituto Giannina Gaslini, Genova, Italy
| | - Fabio Malavasi
- Laboratory of Immunogenetics, Department of Medical Sciences, Turin, Italy.,CeRMS, University of Torino, Turin, Italy
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6
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Rodríguez-Alba JC, Abrego-Peredo A, Gallardo-Hernández C, Pérez-Lara J, Santiago-Cruz JW, Jiang JW, Espinosa E. HIV Disease Progression: Overexpression of the Ectoenzyme CD38 as a Contributory Factor? Bioessays 2019; 41:e1800128. [PMID: 30537007 PMCID: PMC6545924 DOI: 10.1002/bies.201800128] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Revised: 11/02/2018] [Indexed: 12/16/2022]
Abstract
Despite abundant evidence associating CD38 overexpression and CD4 T cell depletion in HIV infection, no causal relation has been investigated. To address this issue, a series of mechanisms are proposed, supported by evidence from different fields, by which CD38 overexpression can facilitate CD4 T cell depletion in HIV infection. According to this model, increased catalytic activity of CD38 may reduce CD4 T cells' cytoplasmic nicotin-amide adenine dinucleotide (NAD), leading to a chronic Warburg effect. This will reduce mitochondrial function. Simultaneously, CD38's catalytic products ADPR and cADPR may be transported to the cytoplasm, where they can activate calcium channels and increase cytoplasmic Ca2+ concentrations, further altering mitochondrial integrity. These mechanisms will decrease the viability and regenerative capacity of CD4 T cells. These hypotheses can be tested experimentally, and might reveal novel therapeutic targets. Also see the video abstract here https://youtu.be/k1LTyiTKPKs.
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Affiliation(s)
- J. C. Rodríguez-Alba
- Flow Cytometry Core Facility, Instituto de Ciencias de la Salud, Universidad Veracruzana, Xalapa, Mexico
| | - A. Abrego-Peredo
- Doctorado en Ciencias de la Salud, Instituto de Ciencias de la Salud, Universidad Veracruzana, Xalapa, Mexico
| | - C. Gallardo-Hernández
- Doctorado en Ciencias de la Salud, Instituto de Ciencias de la Salud, Universidad Veracruzana, Xalapa, Mexico
| | - J. Pérez-Lara
- Doctorado en Ciencias de la Salud, Instituto de Ciencias de la Salud, Universidad Veracruzana, Xalapa, Mexico
| | - J. W. Santiago-Cruz
- Maestría en Ciencias de la Salud, Instituto de Ciencias de la Salud, Universidad Veracruzana, Xalapa, Mexico
| | - J., W. Jiang
- Department of Microbiology and Immunology, and Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA, 29425
| | - E. Espinosa
- Laboratory of Integrative Immunology, National Institute of Respiratory Diseases (INER), Mexico City, Mexico
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7
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Horenstein AL, Morandi F, Bracci C, Pistoia V, Malavasi F. Functional insights into nucleotide-metabolizing ectoenzymes expressed by bone marrow-resident cells in patients with multiple myeloma. Immunol Lett 2018; 205:40-50. [PMID: 30447309 DOI: 10.1016/j.imlet.2018.11.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 11/09/2018] [Indexed: 12/18/2022]
Abstract
Human myeloma cells grow in a hypoxic acidic niche in the bone marrow. Cross talk among cellular components of this closed niche generates extracellular adenosine, which promotes tumor cell survival. This is achieved through the binding of adenosine to purinergic receptors into complexes that function as an autocrine/paracrine signal factor with immune regulatory activities that i) down-regulate the functions of most immune effector cells and ii) enhance the activity of cells that suppress anti-tumor immune responses, thus facilitating the escape of malignant myeloma cells from immune surveillance. Here we review recent findings confirming that the dominant phenotype for survival of tumor cells is that where the malignant cells have been metabolically reprogrammed for the generation of lactic acidosis in the bone marrow niche. Adenosine triphosphate and nicotinamide-adenine dinucleotide extruded from tumor cells, along with cyclic adenosine monophosphate, are the main intracellular energetic/messenger molecules that serve as leading substrates in the extracellular space for membrane-bound ectonucleotidases metabolizing purine nucleotides to signaling adenosine. Within this mechanistic framework, the adenosinergic substrate conversion can vary significantly according to the metabolic environment. Indeed, the neoplastic expansion of plasma cells exploits both enzymatic networks and hypoxic acidic conditions for migrating and homing to a protected niche and for evading the immune response. The expression of multiple specific adenosine receptors in the niche completes the profile of a complex regulatory framework whose signals modify multiple myeloma and host immune responses.
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Affiliation(s)
- A L Horenstein
- Laboratory of Immunogenetics, Department of Medical Sciences, University of Torino, Italy; CeRMS, University of Torino, Torino, Italy.
| | - F Morandi
- Stem Cell Laboratory and Cell Therapy Center, Istituto Giannina Gaslini, Genova, Italy
| | - C Bracci
- Laboratory of Immunogenetics, Department of Medical Sciences, University of Torino, Italy; CeRMS, University of Torino, Torino, Italy
| | - V Pistoia
- Immunology Area, Pediatric Hospital Bambino Gesù, Rome, Italy
| | - F Malavasi
- Laboratory of Immunogenetics, Department of Medical Sciences, University of Torino, Italy; CeRMS, University of Torino, Torino, Italy
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8
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Matasic DS, Brenner C, London B. Emerging potential benefits of modulating NAD + metabolism in cardiovascular disease. Am J Physiol Heart Circ Physiol 2017; 314:H839-H852. [PMID: 29351465 DOI: 10.1152/ajpheart.00409.2017] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Nicotinamide adenine dinucleotide (NAD+) and related metabolites are central mediators of fuel oxidation and bioenergetics within cardiomyocytes. Additionally, NAD+ is required for the activity of multifunctional enzymes, including sirtuins and poly(ADP-ribose) polymerases that regulate posttranslational modifications, DNA damage responses, and Ca2+ signaling. Recent research has indicated that NAD+ participates in a multitude of processes dysregulated in cardiovascular diseases. Therefore, supplementation of NAD+ precursors, including nicotinamide riboside that boosts or repletes the NAD+ metabolome, may be cardioprotective. This review examines the molecular physiology and preclinical data with respect to NAD+ precursors in heart failure-related cardiac remodeling, ischemic-reperfusion injury, and arrhythmias. In addition, alternative NAD+-boosting strategies and potential systemic effects of NAD+ supplementation with implications on cardiovascular health and disease are surveyed.
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Affiliation(s)
- Daniel S Matasic
- Division of Cardiovascular Medicine, Department of Medicine, University of Iowa , Iowa City, Iowa.,Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa , Iowa City, Iowa.,Abboud Cardiovascular Research Center, University of Iowa , Iowa City, Iowa
| | - Charles Brenner
- Abboud Cardiovascular Research Center, University of Iowa , Iowa City, Iowa.,Department of Biochemistry, Carver College of Medicine, University of Iowa , Iowa City, Iowa
| | - Barry London
- Division of Cardiovascular Medicine, Department of Medicine, University of Iowa , Iowa City, Iowa.,Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa , Iowa City, Iowa.,Abboud Cardiovascular Research Center, University of Iowa , Iowa City, Iowa
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9
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10
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NAD⁺-Metabolizing Ectoenzymes in Remodeling Tumor-Host Interactions: The Human Myeloma Model. Cells 2015; 4:520-37. [PMID: 26393653 PMCID: PMC4588049 DOI: 10.3390/cells4030520] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Revised: 09/09/2015] [Accepted: 09/14/2015] [Indexed: 11/17/2022] Open
Abstract
Nicotinamide adenine dinucleotide (NAD⁺) is an essential co-enzyme reported to operate both intra- and extracellularly. In the extracellular space, NAD⁺ can elicit signals by binding purinergic P2 receptors or it can serve as the substrate for a chain of ectoenzymes. As a substrate, it is converted to adenosine (ADO) and then taken up by the cells, where it is transformed and reincorporated into the intracellular nucleotide pool. Nucleotide-nucleoside conversion is regulated by membrane-bound ectoenzymes. CD38, the main mammalian enzyme that hydrolyzes NAD⁺, belongs to the ectoenzymatic network generating intracellular Ca(2+)-active metabolites. Within this general framework, the extracellular conversion of NAD⁺ can vary significantly according to the tissue environment or pathological conditions. Accumulating evidence suggests that tumor cells exploit such a network for migrating and homing to protected areas and, even more importantly, for evading the immune response. We report on the experience of this lab to exploit human multiple myeloma (MM), a neoplastic expansion of plasma cells, as a model to investigate these issues. MM cells express high levels of surface CD38 and grow in an environment prevalently represented by closed niches hosted in the bone marrow (BM). An original approach of this study derives from the recent use of the clinical availability of therapeutic anti-CD38 monoclonal antibodies (mAbs) in perturbing tumor viability and enzymatic functions in conditions mimicking what happens in vivo.
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11
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Ramos I, Reich A, Wessel GM. Two-pore channels function in calcium regulation in sea star oocytes and embryos. Development 2014; 141:4598-609. [PMID: 25377554 DOI: 10.1242/dev.113563] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Egg activation at fertilization is an excellent process for studying calcium regulation. Nicotinic acid adenine dinucleotide-phosphate (NAADP), a potent calcium messenger, is able to trigger calcium release, likely through two-pore channels (TPCs). Concomitantly, a family of ectocellular enzymes, the ADP-ribosyl cyclases (ARCs), has emerged as being able to change their enzymatic mode from one of nucleotide cyclization in formation of cADPR to a base-exchange reaction in the generation of NAADP. Using sea star oocytes we gain insights into the functions of endogenously expressed TPCs and ARCs in the context of the global calcium signals at fertilization. Three TPCs and one ARC were found in the sea star (Patiria miniata) that were localized in the cortex of the oocytes and eggs. PmTPCs were localized in specialized secretory organelles called cortical granules, and PmARCs accumulated in a different, unknown, set of vesicles, closely apposed to the cortical granules in the egg cortex. Using morpholino knockdown of PmTPCs and PmARC in the oocytes, we found that both calcium regulators are essential for early embryo development, and that knockdown of PmTPCs leads to aberrant construction of the fertilization envelope at fertilization and changes in cortical granule pH. The calcium signals at fertilization are not significantly altered when individual PmTPCs are silenced, but the timing and shape of the cortical flash and calcium wave are slightly changed when the expression of all three PmTPCs is perturbed concomitantly, suggesting a cooperative activity among TPC isoforms in eliciting calcium signals that may influence localized physiological activities.
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Affiliation(s)
- Isabela Ramos
- Department of Molecular Biology, Cellular Biology, and Biochemistry, Brown University, Providence, RI 02912, USA Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941, Brazil
| | - Adrian Reich
- Department of Molecular Biology, Cellular Biology, and Biochemistry, Brown University, Providence, RI 02912, USA
| | - Gary M Wessel
- Department of Molecular Biology, Cellular Biology, and Biochemistry, Brown University, Providence, RI 02912, USA
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12
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Zhao YJ, Zhu WJ, Wang XW, Zhang LH, Lee HC. Determinants of the membrane orientation of a calcium signaling enzyme CD38. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2014; 1853:2095-103. [PMID: 25447548 DOI: 10.1016/j.bbamcr.2014.10.028] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/06/2014] [Revised: 10/25/2014] [Accepted: 10/29/2014] [Indexed: 01/08/2023]
Abstract
CD38 catalyzes the synthesis of two structurally distinct messengers for Ca²⁺-mobilization, cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP), from cytosolic substrates, NAD and NADP, respectively. CD38 is generally thought of as a type II membrane protein with its catalytic site facing outside. We recently showed that CD38 exists, instead, in two opposite membrane orientations. The determinant for the membrane topology is unknown. Here, specific antibodies against type III CD38 were designed and produced. We show that mutating the positively charged residues in the N-terminal tail of CD38 converted its orientation to type III, with the catalytic domain facing the cytosol and it was fully active in producing intracellular cADPR. Changing the serine residues to aspartate, which is functionally equivalent to phosphorylation, had a similar effect. The mutated CD38 was expressed intracellularly and was un-glycosylated. The membrane topology could also be modulated by changing the highly conserved di-cysteine. The results indicate that the net charge of the N-terminal segment is important in determining the membrane topology of CD38 and that the type III orientation can be a functional form of CD38 for Ca²⁺-signaling. This article is part of a Special Issue entitled: 13th European Symposium on Calcium.
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Affiliation(s)
- Yong Juan Zhao
- School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, 2199 Lishui Road, Nanshan District, Shenzhen, China; Department of Physiology, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong.
| | - Wen Jie Zhu
- School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, 2199 Lishui Road, Nanshan District, Shenzhen, China
| | - Xian Wang Wang
- Functional Laboratory, School of Medicine, Yangtze University, 1 Nanhuan Road, Jingzhou, Hubei China
| | - Li-He Zhang
- School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, 2199 Lishui Road, Nanshan District, Shenzhen, China; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing, China
| | - Hon Cheung Lee
- School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, 2199 Lishui Road, Nanshan District, Shenzhen, China.
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Wei W, Graeff R, Yue J. Roles and mechanisms of the CD38/cyclic adenosine diphosphate ribose/Ca 2+ signaling pathway. World J Biol Chem 2014; 5:58-67. [PMID: 24600514 PMCID: PMC3942542 DOI: 10.4331/wjbc.v5.i1.58] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Revised: 11/09/2013] [Accepted: 12/19/2013] [Indexed: 02/05/2023] Open
Abstract
Mobilization of intracellular Ca2+ stores is involved in many diverse cell functions, including: cell proliferation; differentiation; fertilization; muscle contraction; secretion of neurotransmitters, hormones and enzymes; and lymphocyte activation and proliferation. Cyclic adenosine diphosphate ribose (cADPR) is an endogenous Ca2+ mobilizing nucleotide present in many cell types and species, from plants to animals. cADPR is formed by ADP-ribosyl cyclases from nicotinamide adenine dinucleotide. The main ADP-ribosyl cyclase in mammals is CD38, a multi-functional enzyme and a type II membrane protein. It has been shown that many extracellular stimuli can induce cADPR production that leads to calcium release or influx, establishing cADPR as a second messenger. cADPR has been linked to a wide variety of cellular processes, but the molecular mechanisms regarding cADPR signaling remain elusive. The aim of this review is to summarize the CD38/cADPR/Ca2+ signaling pathway, focusing on the recent advances involving the mechanism and physiological functions of cADPR-mediated Ca2+ mobilization.
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14
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Liu M, Gu L, Sulkin MS, Liu H, Jeong EM, Greener I, Xie A, Efimov IR, Dudley SC. Mitochondrial dysfunction causing cardiac sodium channel downregulation in cardiomyopathy. J Mol Cell Cardiol 2013; 54:25-34. [PMID: 23123323 PMCID: PMC3595554 DOI: 10.1016/j.yjmcc.2012.10.011] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2012] [Revised: 10/04/2012] [Accepted: 10/24/2012] [Indexed: 01/01/2023]
Abstract
Cardiomyopathy is associated with cardiac Na(+) channel downregulation that may contribute to arrhythmias. Previously, we have shown that elevated intracellular NADH causes a decrease in cardiac Na(+) current (I(Na)) signaled by an increase in mitochondrial reactive oxygen species (ROS). In this study, we tested whether the NADH-mitochondria ROS pathway was involved in the reduction of I(Na) in a nonischemic cardiomyopathic model and correlated the findings with myopathic human hearts. Nonischemic cardiomyopathy was induced in C57BL/6 mice by hypertension after unilateral nephrectomy, deoxycorticosterone acetate (DOCA) pellet implantation, and salt water substitution. Sham operated mice were used as controls. After six weeks, heart tissue and ventricular myocytes isolated from mice were utilized for whole cell patch clamp recording, NADH/NAD(+) level measurements, and mitochondrial ROS monitoring with confocal microscopy. Human explanted hearts were studied using optical mapping. Compared to the sham mice, the arterial blood pressure was higher, the left ventricular volume was significantly enlarged (104.7±3.9 vs. 87.9±6.1 μL, P<0.05), and the ejection fraction was reduced (37.1±1.8% vs. 49.4±3.7%, P<0.05) in DOCA mice. Both the whole cell and cytosolic NADH level were increased (279±70% and 123±2% of sham, respectively, P<0.01), I(Na) was decreased (60±10% of sham, P<0.01), and mitochondrial ROS overproduction was observed (2.9±0.3-fold of sham, P<0.01) in heart tissue and myocytes of myopathic mice vs. sham. Treatment of myocytes with NAD(+) (500 μM), mitoTEMPO (10 μM), chelerythrine (50 μM), or forskolin (5 μM) restored I(Na) back to the level of sham. Injection of NAD(+) (100mg/kg) or mitoTEMPO (0.7 mg/kg) twice (at 24h and 1h before myocyte isolation) to animals also restored I(Na). All treatments simultaneously reduced mitochondrial ROS levels to that of controls. CD38 was found to transduce the extracellular NAD(+) signal. Correlating with the mouse model, failing human hearts showed a reduction in conduction velocity that improved with NAD(+). Nonischemic cardiomyopathy was associated with elevated NADH level, PKC activation, mitochondrial ROS overproduction, and a concomitant decrease in I(Na). Reducing mitochondrial ROS by application of NAD(+), mitoTEMPO, PKC inhibitors, or PKA activators, restored I(Na). NAD(+) improved conduction velocity in human myopathic hearts.
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Affiliation(s)
- Man Liu
- Section of Cardiology, Department of Medicine, University of Illinois at Chicago, USA
- the Jesse Brown VAMC, Chicago, IL, USA
| | - Lianzhi Gu
- Section of Cardiology, Department of Medicine, University of Illinois at Chicago, USA
- the Jesse Brown VAMC, Chicago, IL, USA
| | - Matthew S. Sulkin
- Department of Biomedical Engineering, Washington University in Saint Louis, USA
| | - Hong Liu
- Section of Cardiology, Department of Medicine, University of Illinois at Chicago, USA
- the Jesse Brown VAMC, Chicago, IL, USA
| | - Euy-Myoung Jeong
- Section of Cardiology, Department of Medicine, University of Illinois at Chicago, USA
| | - Ian Greener
- Section of Cardiology, Department of Medicine, University of Illinois at Chicago, USA
| | - An Xie
- Section of Cardiology, Department of Medicine, University of Illinois at Chicago, USA
| | - Igor R. Efimov
- Department of Biomedical Engineering, Washington University in Saint Louis, USA
| | - Samuel C. Dudley
- Section of Cardiology, Department of Medicine, University of Illinois at Chicago, USA
- the Jesse Brown VAMC, Chicago, IL, USA
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15
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Ramos I, Wessel GM. Calcium pathway machinery at fertilization in echinoderms. Cell Calcium 2012; 53:16-23. [PMID: 23218671 DOI: 10.1016/j.ceca.2012.11.011] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Revised: 11/07/2012] [Accepted: 11/09/2012] [Indexed: 01/01/2023]
Abstract
Calcium signaling in cells directs diverse physiological processes. The calcium waves triggered by fertilization is a highly conserved calcium signaling event essential for egg activation, and has been documented in every egg tested. This activity is one of the few highly conserved events of egg activation through the course of evolution. Echinoderm eggs, as well as many other cell types, have three main intracellular Ca(2+) mobilizing messengers - IP3, cADPR and NAADP. Both cADPR and NAADP were identified as Ca(2+) mobilizing messengers using the sea urchin egg homogenate, and this experimental system, along with the intact urchin and starfish oocyte/egg, continues to be a vital tool for investigating the mechanism of action of calcium signals. While many of the major regulatory steps of the IP3 pathway are well resolved, both cADPR and NAADP remain understudied in terms of our understanding of the fundamental process of egg activation at fertilization. Recently, NAADP has been shown to trigger Ca(2+) release from acidic vesicles, separately from the ER, and a new class of calcium channels, the two-pore channels (TPCs), was identified as the likely targets for this messenger. Moreover, it was found that both cADPR and NAADP can be synthesized by the same family of enzymes, the ADP-rybosyl cyclases (ARCs). In this context of increasing amount of information, the potential coupling and functional roles of different messengers, intracellular stores and channels in the formation of the fertilization calcium wave in echinoderms will be critically evaluated.
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Affiliation(s)
- Isabela Ramos
- Department of Molecular Biology, Cellular Biology, and Biochemistry, Brown University, Providence, RI 02912, USA
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16
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Zhao Y, Graeff R, Lee HC. Roles of cADPR and NAADP in pancreatic cells. Acta Biochim Biophys Sin (Shanghai) 2012; 44:719-29. [PMID: 22677461 DOI: 10.1093/abbs/gms044] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) are Ca(2+)-mobilizing nucleotides that were discovered in the late 1980s. Two decades of investigations have built up a considerable understanding about these two molecules that are related because both are derived from pyridine nucleotides and known to be generated by CD38/ADP-ribosyl cyclases. cADPR has been shown to target the ryanodine receptors in the endoplasmic reticulum whereas NAADP stimulates the two-pore channels in the endo-lysosomes. Accumulating results indicate that cADPR and NAADP are second messenger molecules mediating Ca(2+) signaling activated by a wide range of agonists. This article reviews what is known about these two molecules, especially regarding their signaling roles in the pancreatic cells.
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Affiliation(s)
- Yongjuan Zhao
- Department of Physiology, The University of Hong Kong, Hong Kong, China
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17
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Schmid F, Fliegert R, Westphal T, Bauche A, Guse AH. Nicotinic acid adenine dinucleotide phosphate (NAADP) degradation by alkaline phosphatase. J Biol Chem 2012; 287:32525-34. [PMID: 22851169 DOI: 10.1074/jbc.m112.362715] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Nicotinic acid adenine dinucleotide phosphate (NAADP) is a ubiquitous second messenger providing a Ca(2+) trigger in a wide range of cell types. However, its metabolism is not well understood. Here, we demonstrate the presence of endogenous NAADP in HeLa cells. CD38, a promiscuous enzyme described to be involved in NAADP metabolism, was not detectable in HeLa cells. In cell-free extracts of HeLa cells, NAADP was degraded to nicotinic acid adenine dinucleotide (NAAD). The enzyme was enriched in membranes (10,000 × g pellet) and displayed characteristics typical of alkaline phosphatase (AP), e.g. pH optimum at 8-9 and sensitivity to the inhibitors L-homoarginine and L-leucine. Importantly, NAADP at physiological concentrations (50-100 nM) was degraded to NAAD. Expression of AP isoenzymes was analyzed in HeLa cells. Based on the results together with inhibitor studies, the placental AP isoform emerged as the best candidate for NAADP degradation in HeLa cells. In contrast to HeLa cells, Jurkat T cells or HEK293 cells did not express any AP isoenzymes and did not display any NAADP 2'-phosphatase activity. Finally, the placental AP isoform was expressed heterologously in HEK293 cells, resulting in reconstitution of NAADP 2'-phosphatase activity in cell-free extracts. On the basis of the results, we provide evidence for AP as the metabolizing enzyme of NAADP in cells that do not express CD38.
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Affiliation(s)
- Frederike Schmid
- The Calcium Signalling Group, Department of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
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18
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Lee HC. Cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate (NAADP) as messengers for calcium mobilization. J Biol Chem 2012; 287:31633-40. [PMID: 22822066 DOI: 10.1074/jbc.r112.349464] [Citation(s) in RCA: 161] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate were discovered >2 decades ago. That they are second messengers for mobilizing Ca(2+) stores has since been firmly established. Separate stores and distinct Ca(2+) channels are targeted, with cyclic ADP-ribose acting on the ryanodine receptors in the endoplasmic reticulum, whereas nicotinic acid adenine dinucleotide phosphate mobilizes the endolysosomes via the two-pore channels. Despite the structural and functional differences, both messengers are synthesized by a ubiquitous enzyme, CD38, whose crystal structure and catalytic mechanism have now been well elucidated. How this novel signaling enzyme is regulated remains largely unknown and is the focus of this minireview.
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Affiliation(s)
- Hon Cheung Lee
- Department of Physiology, University of Hong Kong, Hong Kong, China.
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19
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Rosen D, Bloor-Young D, Squires J, Parkesh R, Waters G, Vasudevan SR, Lewis AM, Churchill GC. Synthesis and use of cell-permeant cyclic ADP-ribose. Biochem Biophys Res Commun 2012; 418:353-8. [PMID: 22274607 DOI: 10.1016/j.bbrc.2012.01.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2012] [Accepted: 01/06/2012] [Indexed: 12/13/2022]
Abstract
Cyclic ADP-ribose (cADPR) is a second messenger that acts on ryanodine receptors to mobilize Ca(2+). cADPR has a net negative charge at physiological pH making it not passively membrane permeant thereby requiring it to be injected, electroporated or loaded via liposomes. Such membrane impermeance of other charged intracellular messengers (including cyclic AMP, inositol 1,4,5-trisphosphate and nicotinic acid adenine dinucleotide phosphate) and fluorescent dyes (including fura-2 and fluorescein) has been overcome by synthesizing masked analogs (prodrugs), which are passively permeant and hydrolyzed to the parent compound inside cells. We now report the synthesis and biological activity of acetoxymethyl (AM) and butoxymethyl (BM) analogs of cADPR. Extracellular addition of cADPR-AM or cADPR-BM to neuronal cells in primary culture or PC12 neuroblastoma cells induced increases in cytosolic Ca(2+). Pre-incubation of PC12 cells with thapsigargin, ryanodine or caffeine eliminated the response to cADPR-AM, whereas the response still occurred in the absence of extracellular Ca(2+). Combined, these data demonstrate that masked cADPR analogs are cell-permeant and biologically active. We hope these cell-permeant tools will facilitate cADPR research and reveal its diverse physiological functions.
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Affiliation(s)
- Daniel Rosen
- University of Oxford, Department of Pharmacology, Mansfield Road, Oxford OX1 3QT, UK
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20
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Song EK, Rah SY, Lee YR, Yoo CH, Kim YR, Yeom JH, Park KH, Kim JS, Kim UH, Han MK. Connexin-43 hemichannels mediate cyclic ADP-ribose generation and its Ca2+-mobilizing activity by NAD+/cyclic ADP-ribose transport. J Biol Chem 2011; 286:44480-90. [PMID: 22033928 DOI: 10.1074/jbc.m111.307645] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The ADP-ribosyl cyclase CD38 whose catalytic domain resides in outside of the cell surface produces the second messenger cyclic ADP-ribose (cADPR) from NAD(+). cADPR increases intracellular Ca(2+) through the intracellular ryanodine receptor/Ca(2+) release channel (RyR). It has been known that intracellular NAD(+) approaches ecto-CD38 via its export by connexin (Cx43) hemichannels, a component of gap junctions. However, it is unclear how cADPR extracellularly generated by ecto-CD38 approaches intracellular RyR although CD38 itself or nucleoside transporter has been proposed to import cADPR. Moreover, it has been unknown what physiological stimulation can trigger Cx43-mediated export of NAD(+). Here we demonstrate that Cx43 hemichannels, but not CD38, import cADPR to increase intracellular calcium through RyR. We also demonstrate that physiological stimulation such as Fcγ receptor (FcγR) ligation induces calcium mobilization through three sequential steps, Cx43-mediated NAD(+) export, CD38-mediated generation of cADPR and Cx43-mediated cADPR import in J774 cells. Protein kinase A (PKA) activation also induced calcium mobilization in the same way as FcγR stimulation. FcγR stimulation-induced calcium mobilization was blocked by PKA inhibition, indicating that PKA is a linker between FcγR stimulation and NAD(+)/cADPR transport. Cx43 knockdown blocked extracellular cADPR import and extracellular cADPR-induced calcium mobilization in J774 cells. Cx43 overexpression in Cx43-negative cells conferred extracellular cADPR-induced calcium mobilization by the mediation of cADPR import. Our data suggest that Cx43 has a dual function exporting NAD(+) and importing cADPR into the cell to activate intracellular calcium mobilization.
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Affiliation(s)
- Eun-Kyung Song
- Departments of Microbiology and Biochemistry, Chonbuk National University Medical School and Hospital, Jeonju 561-182, Korea
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21
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Lee HC. Cyclic ADP-ribose and NAADP: fraternal twin messengers for calcium signaling. SCIENCE CHINA-LIFE SCIENCES 2011; 54:699-711. [PMID: 21786193 DOI: 10.1007/s11427-011-4197-3] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2011] [Accepted: 06/10/2011] [Indexed: 12/17/2022]
Abstract
The concept advanced by Berridge and colleagues that intracellular Ca(2+)-stores can be mobilized in an agonist-dependent and messenger (IP(3))-mediated manner has put Ca(2+)-mobilization at the center stage of signal transduction mechanisms. During the late 1980s, we showed that Ca(2+)-stores can be mobilized by two other messengers unrelated to inositol trisphosphate (IP(3)) and identified them as cyclic ADP-ribose (cADPR), a novel cyclic nucleotide from NAD, and nicotinic acid adenine dinucleotide phosphate (NAADP), a linear metabolite of NADP. Their messenger functions have now been documented in a wide range of systems spanning three biological kingdoms. Accumulated evidence indicates that the target of cADPR is the ryanodine receptor in the sarco/endoplasmic reticulum, while that of NAADP is the two pore channel in endolysosomes.As cADPR and NAADP are structurally and functionally distinct, it is remarkable that they are synthesized by the same enzyme. They are thus fraternal twin messengers. We first identified the Aplysia ADP-ribosyl cyclase as one such enzyme and, through homology, found its mammalian homolog, CD38. Gene knockout in mice confirms the important roles of CD38 in diverse physiological functions from insulin secretion, susceptibility to bacterial infection, to social behavior of mice through modulating neuronal oxytocin secretion. We have elucidated the catalytic mechanisms of the Aplysia cyclase and CD38 to atomic resolution by crystallography and site-directed mutagenesis. This article gives a historical account of the cADPR/NAADP/CD38-signaling pathway and describes current efforts in elucidating the structure and function of its components.
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Affiliation(s)
- Hon Cheung Lee
- Department of Physiology, University of Hong Kong, Hong Kong, China.
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22
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Zhao YJ, Zhang HM, Lam CMC, Hao Q, Lee HC. Cytosolic CD38 protein forms intact disulfides and is active in elevating intracellular cyclic ADP-ribose. J Biol Chem 2011; 286:22170-7. [PMID: 21524995 DOI: 10.1074/jbc.m111.228379] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
CD38 catalyzes the synthesis of cyclic ADP-ribose (cADPR), a Ca(2+) messenger responsible for regulating a wide range of physiological functions. It is generally regarded as an ectoenzyme, but its intracellular localization has also been well documented. It is not known if internal CD38 is enzymatically active and contributes to the Ca(2+) signaling function. In this study, we engineered a novel soluble form of CD38 that can be efficiently expressed in the cytosol and use cytosolic NAD as a substrate to produce cADPR intracellularly. The activity of the engineered CD38 could be decreased by mutating the catalytic residue Glu-226 and increased by the double mutation E146A/T221F, which increased its cADPR synthesis activity by >11-fold. Remarkably, the engineered CD38 exhibited the ability to form the critical disulfide linkages required for its enzymatic activity. This was verified by using a monoclonal antibody generated against a critical disulfide, Cys-254-Cys-275. The specificity of the antibody was established by x-ray crystallography and site-directed mutagenesis. The engineered CD38 is thus a novel example challenging the general belief that cytosolic proteins do not possess disulfides. As a further refinement of this approach, the engineered CD38 was placed under the control of tetracycline using an autoregulated construct. This study has set the stage for in vivo manipulation of cADPR metabolism.
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Affiliation(s)
- Yong Juan Zhao
- Department of Physiology, The University of Hong Kong, Hong Kong, China
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23
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Rah SY, Mushtaq M, Nam TS, Kim SH, Kim UH. Generation of cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate by CD38 for Ca2+ signaling in interleukin-8-treated lymphokine-activated killer cells. J Biol Chem 2010; 285:21877-87. [PMID: 20442403 DOI: 10.1074/jbc.m109.066290] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
We have previously demonstrated that cyclic ADP-ribose (cADPR) is a calcium signaling messenger in interleukin 8 (IL-8)-induced lymphokine-activated killer (LAK) cells. In this study we examined the possibility that IL-8 activates CD38 to produce another messenger, nicotinic acid adenine dinucleotide phosphate (NAADP), in LAK cells, and we showed that IL-8 induced NAADP formation after cADPR production. These calcium signaling messengers were not produced when LAK cells prepared from CD38 knock-out mice were treated with IL-8, indicating that the synthesis of both NAADP and cADPR is catalyzed by CD38 in LAK cells. Application of cADPR to LAK cells induced NAADP production, whereas NAADP failed to increase intracellular cADPR levels, confirming that the production of cADPR precedes that of NAADP in IL-8-treated LAK cells. Moreover, NAADP increased intracellular Ca(2+) signaling as well as cell migration, which was completely blocked by bafilomycin A1, suggesting that NAADP is generated in lysosome-related organelles after cADPR production. IL-8 or exogenous cADPR, but not NAADP, increased intracellular cAMP levels. cGMP analog, 8-(4-chlorophenylthio)-guanosine 3',5'-cyclic monophosphate, increased both cADPR and NAADP production, whereas the cAMP analog, 8-(4-chlorophenylthio)-cAMP, increased only NAADP production, suggesting that cAMP is essential for IL-8-induced NAADP formation. Furthermore, activation of Rap1, a downstream molecule of Epac, was required for IL-8-induced NAADP formation in LAK cells. Taken together, our data suggest that IL-8-induced NAADP production is mediated by CD38 activation through the actions of cAMP/Epac/protein kinase A/Rap1 in LAK cells and that NAADP plays a key role in Ca(2+) signaling of IL-8-induced LAK cell migration.
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Affiliation(s)
- So-Young Rah
- Departments of Biochemistry, Chonbuk National University Medical School, Jeonju 561-182, Republic of Korea
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24
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Magnone M, Bruzzone S, Guida L, Damonte G, Millo E, Scarfì S, Usai C, Sturla L, Palombo D, De Flora A, Zocchi E. Abscisic acid released by human monocytes activates monocytes and vascular smooth muscle cell responses involved in atherogenesis. J Biol Chem 2009; 284:17808-17818. [PMID: 19332545 PMCID: PMC2719419 DOI: 10.1074/jbc.m809546200] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2008] [Revised: 03/18/2009] [Indexed: 01/08/2023] Open
Abstract
Abscisic acid (ABA) is a phytohormone recently identified as a new endogenous pro-inflammatory hormone in human granulocytes. Here we report the functional activation of human monocytes and vascular smooth muscle cells by ABA. Incubation of monocytes with ABA evokes an intracellular Ca2+ rise through the second messenger cyclic ADP-ribose, leading to NF-kappaB activation and consequent increase of cyclooxygenase-2 expression and prostaglandin E2 production and enhanced release of MCP-1 (monocyte chemoattractant protein-1) and of metalloprotease-9, all events reportedly involved in atherogenesis. Moreover, monocytes release ABA when exposed to thrombin-activated platelets, a condition occurring at the injured vascular endothelium; monocyte-derived ABA behaves as an autocrine and paracrine pro-inflammatory hormone-stimulating monocyte migration and MCP-1 release, as well as vascular smooth muscle cells migration and proliferation. These results, and the presence of ABA in human arterial plaques at a 10-fold higher concentration compared with normal arterial tissue, identify ABA as a new signal molecule involved in the development of atherosclerosis and suggest a possible new target for anti-atherosclerotic therapy.
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Affiliation(s)
- Mirko Magnone
- From the Department of Experimental Medicine, Section of Biochemistry and Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 1, 16132 Genova
| | - Santina Bruzzone
- From the Department of Experimental Medicine, Section of Biochemistry and Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 1, 16132 Genova
- the Advanced Biotechnology Center, Largo Rosanna Benzi 1, 16132 Genova
| | - Lucrezia Guida
- From the Department of Experimental Medicine, Section of Biochemistry and Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 1, 16132 Genova
| | - Gianluca Damonte
- From the Department of Experimental Medicine, Section of Biochemistry and Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 1, 16132 Genova
| | - Enrico Millo
- From the Department of Experimental Medicine, Section of Biochemistry and Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 1, 16132 Genova
| | - Sonia Scarfì
- From the Department of Experimental Medicine, Section of Biochemistry and Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 1, 16132 Genova
- the Advanced Biotechnology Center, Largo Rosanna Benzi 1, 16132 Genova
| | - Cesare Usai
- the Institute of Biophysics, Consiglio Nazionale delle Ricerche, Via De Marini 6, 16149 Genova, and
| | - Laura Sturla
- From the Department of Experimental Medicine, Section of Biochemistry and Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 1, 16132 Genova
| | - Domenico Palombo
- the Vascular and Endovascular Surgery Unit, San Martino Hospital, 16132 Genova, Italy
| | - Antonio De Flora
- From the Department of Experimental Medicine, Section of Biochemistry and Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 1, 16132 Genova
| | - Elena Zocchi
- From the Department of Experimental Medicine, Section of Biochemistry and Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 1, 16132 Genova
- the Advanced Biotechnology Center, Largo Rosanna Benzi 1, 16132 Genova
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25
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Bodrato N, Franco L, Fresia C, Guida L, Usai C, Salis A, Moreschi I, Ferraris C, Verderio C, Basile G, Bruzzone S, Scarfì S, De Flora A, Zocchi E. Abscisic acid activates the murine microglial cell line N9 through the second messenger cyclic ADP-ribose. J Biol Chem 2009; 284:14777-14787. [PMID: 19329433 PMCID: PMC2685659 DOI: 10.1074/jbc.m802604200] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2008] [Revised: 02/06/2009] [Indexed: 02/04/2023] Open
Abstract
Abscisic acid (ABA) is a phytohormone regulating important functions in higher plants, notably responses to abiotic stress. Recently, chemical or physical stimulation of human granulocytes was shown to induce production and release of endogenous ABA, which activates specific cell functions. Here we provide evidence that ABA stimulates several functional activities of the murine microglial cell line N9 (NO and tumor necrosis factor-alpha production, cell migration) through the second messenger cyclic ADP-ribose and an increase of intracellular calcium. ABA production and release occur in N9 cells stimulated with bacterial lipopolysaccharide, phorbol myristate acetate, the chemoattractant peptide f-MLP, or beta-amyloid, the primary plaque component in Alzheimer disease. Finally, ABA priming stimulates N9 cell migration toward beta-amyloid. These results indicate that ABA is a pro-inflammatory hormone inducing autocrine microglial activation, potentially representing a new target for anti-inflammatory therapies aimed at limiting microglia-induced tissue damage in the central nervous system.
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Affiliation(s)
- Nicoletta Bodrato
- Department of Experimental Medicine, Section of Biochemistry, and Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV/1, 16132 Genova, Italy
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26
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The role of dietary niacin intake and the adenosine-5'-diphosphate-ribosyl cyclase enzyme CD38 in spatial learning ability: is cyclic adenosine diphosphate ribose the link between diet and behaviour? Nutr Res Rev 2009; 21:42-55. [PMID: 19079853 DOI: 10.1017/s0954422408945182] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
The pyridine nucleotide NAD+ is derived from dietary niacin and serves as the substrate for the synthesis of cyclic ADP-ribose (cADPR), an intracellular Ca signalling molecule that plays an important role in synaptic plasticity in the hippocampus, a region of the brain involved in spatial learning. cADPR is formed in part via the activity of the ADP-ribosyl cyclase enzyme CD38, which is widespread throughout the brain. In the present review, current evidence of the relationship between dietary niacin and behaviour is presented following investigations of the effect of niacin deficiency, pharmacological nicotinamide supplementation and CD38 gene deletion on brain nucleotides and spatial learning ability in mice and rats. In young male rats, both niacin deficiency and nicotinamide supplementation significantly altered brain NAD+ and cADPR, both of which were inversely correlated with spatial learning ability. These results were consistent across three different models of niacin deficiency (pair feeding, partially restricted feeding and niacin recovery). Similar changes in spatial learning ability were observed in Cd38- / - mice, which also showed decreases in brain cADPR. These findings suggest an inverse relationship between spatial learning ability, dietary niacin intake and cADPR, although a direct link between cADPR and spatial learning ability is still missing. Dietary niacin may therefore play a role in the molecular events regulating learning performance, and further investigations of niacin intake, CD38 and cADPR may help identify potential molecular targets for clinical intervention to enhance learning and prevent or reverse cognitive decline.
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27
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Grahnert A, Klein C, Hauschildt S. Involvement of P2X receptors in the NAD(+)-induced rise in [Ca (2+)] (i) in human monocytes. Purinergic Signal 2009; 5:309-19. [PMID: 19221895 DOI: 10.1007/s11302-009-9144-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2008] [Accepted: 01/27/2009] [Indexed: 01/06/2023] Open
Abstract
In the present study, we show that the extracellular addition of nicotinamide adenine dinucleotide (NAD(+)) induces a transient rise in [Ca(2+)](i) in human monocytes caused by an influx of extracellular calcium. The NAD(+)-induced Ca(2+) response was prevented by adenosine triphosphate (ATP), suggesting the involvement of ATP receptors. Of the two subtypes of ATP receptors (P2X and P2Y), the P2X receptors were considered the most likely candidates. By the use of subtype preferential agonists and antagonists, we identified P2X(1), P2X(4), and P2X(7) receptors being engaged in the NAD(+)-induced rise in [Ca(2+)](i). Among the P2X receptor subtypes, the P2X(7) receptor is unique in facilitating the induction of nonselective pores that allow entry of ethidium upon stimulation with ATP. In monocytes, opening of P2X(7) receptor-dependent pores strongly depends on specific ionic conditions. Measuring pore formation in response to NAD(+), we found that NAD(+) unlike ATP lacks the ability to induce this pore-forming response. Whereas as little as 100 muM ATP was sufficient to activate the nonselective pore, NAD(+) at concentrations up to 2 mM had no effect. Taken together, these data indicate that despite similarities in the action of extracellular NAD(+) and ATP there are nucleotide-specific variations. So far, common and distinct features of the two nucleotides are only beginning to be understood.
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Affiliation(s)
- Anja Grahnert
- Department of Immunobiology, Institute of Biology II, University of Leipzig, Talstrasse 33, 04103, Leipzig, Germany
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28
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Scarfì S, Ferraris C, Fruscione F, Fresia C, Guida L, Bruzzone S, Usai C, Parodi A, Millo E, Salis A, Burastero G, De Flora A, Zocchi E. Cyclic ADP-ribose-mediated expansion and stimulation of human mesenchymal stem cells by the plant hormone abscisic acid. Stem Cells 2008; 26:2855-2864. [PMID: 18687991 DOI: 10.1634/stemcells.2008-0488] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Abscisic acid (ABA) is a phytohormone involved in fundamental processes in higher plants. Endogenous ABA biosynthesis occurs also in lower Metazoa, in which ABA regulates several physiological functions by activating ADP-ribosyl cyclase (ADPRC) and causing overproduction of the Ca(2+)-mobilizing second messenger cyclic ADP-ribose (cADPR), thereby enhancing intracellular Ca(2+) concentration ([Ca(2+)](i)). Recently, production and release of ABA have been demonstrated to take place also in human granulocytes, where ABA behaves as a proinflammatory hormone through the same cADPR/[Ca(2+)](i) signaling pathway described in plants and in lower Metazoa. On the basis of the fact that human mesenchymal stem cells (MSC) express ADPRC activity, we investigated the effects of ABA and of its second messenger, cADPR, on purified human MSC. Both ABA and cADPR stimulate the in vitro expansion of MSC without affecting differentiation. The underlying mechanism involves a signaling cascade triggered by ABA binding to a plasma membrane receptor and consequent cyclic AMP-mediated activation of ADPRC and of the cADPR/[Ca(2+)](i) system. Moreover, ABA stimulates the following functional activities of MSC: cyclooxygenase 2-catalyzed production of prostaglandin E(2) (PGE(2)), release of several cytokines known to mediate the trophic and immunomodulatory properties of MSC, and chemokinesis. Remarkably, ABA proved to be produced and released by MSC stimulated by specific growth factors (e.g., bone morphogenetic protein-7), by inflammatory cytokines, and by lymphocyte-conditioned medium. These data demonstrate that ABA is an autocrine stimulator of MSC function and suggest that it may participate in the paracrine signaling among MSC, inflammatory/immune cells, and hemopoietic progenitors. Disclosure of potential conflicts of interest is found at the end of this article.
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Affiliation(s)
- Sonia Scarfì
- Department of Experimental Medicine, Section of Biochemistry, Advanced Biotechnology Center, University of Genova, Genova,, Italy.
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29
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Mándi M, Bak J. Nicotinic acid adenine dinucleotide phosphate (NAADP) and Ca2+ mobilization. J Recept Signal Transduct Res 2008; 28:163-84. [PMID: 18569524 DOI: 10.1080/10799890802084085] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Many physiological processes are controlled by a great diversity of Ca2+ signals that depend on Ca2+ entry into the cell and/or Ca2+ release from internal Ca2+ stores. Ca2+ mobilization from intracellular stores is gated by a family of messengers including inositol-1,4,5-trisphosphate (InsP3), cyclic ADP-ribose (cADPR), and nicotinic acid adenine dinucleotide phosphate (NAADP). There is increasing evidence for a novel intracellular Ca2+ release channel that may be targeted by NAADP and that displays properties distinctly different from the well-characterized InsP3 and ryanodine receptors. These channels appear to localize on a wider range of intracellular organelles, including the acidic Ca2+ stores. Activation of the NAADP-sensitive Ca2+ channels evokes complex changes in cytoplasmic Ca2+ levels by means of channel chatter with other intracellular Ca2+ channels. The recent demonstration of changes in intracellular NAADP levels in response to physiologically relevant extracellular stimuli highlights the significance of NAADP as an important regulator of intracellular Ca2+ signaling.
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Affiliation(s)
- Miklós Mándi
- Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary.
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Molecular characterization of a novel cell surface ADP-ribosyl cyclase from the sea urchin. Cell Signal 2008; 20:2347-55. [PMID: 18824228 DOI: 10.1016/j.cellsig.2008.09.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2008] [Revised: 08/26/2008] [Accepted: 09/09/2008] [Indexed: 11/24/2022]
Abstract
The sea urchin is an extensively used model system for the study of calcium signalling by the messenger molecules NAADP and cyclic ADP-ribose. Both are synthesized by ADP-ribosyl cyclases but our molecular understanding of these enzymes in the sea urchin is limited. We have recently reported the cloning of an extended family of sea urchin ADP-ribosyl cyclases and shown that one of these enzymes (SpARC1) is active within the endoplasmic reticulum lumen. These studies suggest that production of messengers is compartmentalized. Here we characterize the properties of SpARC2. SpARC2 catalyzed both NAADP and cyclic ADP-ribose production. Unusually, the NAD surrogate, NGD was a poor substrate. In contrast to SpARC1, heterologously expressed SpARC2 localized to the plasma membrane via a glycosylphosphatidylinositol (GPI)-anchor. Transcripts for SpARC2 were readily detectable in sea urchin eggs and a majority of the endogenous membrane bound activity was found to be GPI-anchored. Our data reveal striking differences in the properties of sea urchin ADP-ribosyl cyclases and provide further evidence that messenger production may occur outside of the cytosol.
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Banerjee S, Walseth TF, Borgmann K, Wu L, Bidasee KR, Kannan MS, Ghorpade A. CD38/cyclic ADP-ribose regulates astrocyte calcium signaling: implications for neuroinflammation and HIV-1-associated dementia. J Neuroimmune Pharmacol 2008; 3:154-64. [PMID: 18581239 DOI: 10.1007/s11481-008-9105-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2007] [Accepted: 04/02/2008] [Indexed: 11/25/2022]
Abstract
CD38 is a 45-kD ectoenzyme involved in the synthesis of potent calcium (Ca(2+))-mobilizing agents, cyclic adenosine diphosphate-ribose (cADPR), and nicotinic acid adenine dinucleotide phosphate (NAADP+). In HIV-1-infected patients, increased CD38 expression on CD8+ T cells is linked to immune system activation and progression of HIV-1 infection. However, the role of CD38 upregulation in astrocyte function and HIV-1-associated dementia (HAD-now called HAND: HIV-1-associated neurocognitive disorder) neuropathogenesis is unclear. To these ends, we used interleukin (IL)-1beta and HIV-1gp120 to activate primary human astrocytes and measured CD38 expression using real-time polymerase chain reaction and CD38 function by ADP-ribosyl cyclase activity. We also determined cADPR-mediated changes in single-cell intracellular Ca(2+) transients in activated astrocytes in presence or absence of ethylene glycol tetraacetic acid. CD38 levels were downregulated using CD38 small-interfering RNA (siRNA) and intracellular Ca(2+) concentration ([Ca(2+)](i)) was measured. We previously reported a approximately 20-fold rise in CD38 messenger RNA levels in IL-1beta-activated astrocytes. We extend this observation and report that HIV-1gp120 potentiated CD38 expression in a dose-dependent manner and also increased CD38 enzyme activity in control and IL-1beta-activated astrocytes. We demonstrate higher cADPR levels in IL-1beta-activated astrocytes with a corresponding rise in [Ca(2+)](i) upon cADPR application and its non-hydrolysable analog, 3-deaza-cADPR. In activated astrocytes, pre-treatment with the cADPR-specific antagonist 8-Br-cADPR and CD38 siRNA transfection returned elevated [Ca(2+)](i) to baseline, thus confirming a CD38-cADPR specific response. These data are important for unraveling the mechanisms underlying the role of astrocyte-CD38 in HAD and have broader implications in other inflammatory diseases involving astrocyte activation and CD38 dysregulation.
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Affiliation(s)
- Sugato Banerjee
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
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32
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Morita K, Saida M, Morioka N, Kitayama T, Akagawa Y, Dohi T. Cyclic ADP-ribose mediates formyl methionyl leucyl phenylalanine (fMLP)-induced intracellular Ca(2+) rise and migration of human neutrophils. J Pharmacol Sci 2008; 106:492-504. [PMID: 18344610 DOI: 10.1254/jphs.fp0072083] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
Although cyclic ADP-ribose (cADPR), a novel Ca(2+)-mobilizing mediator, is suggested to be involved in the functions of neutrophils in rodents, its role in human neutrophils remains unclear. The present study examined the ability of cADPR to mobilize Ca(2+) and mediate formyl methionyl leucyl phenylalanine (fMLP)-stimulated increase in cytosolic free Ca(2+) concentration ([Ca(2+)](i)) and migration in human neutrophils. cADPR induced Ca(2+) release from digitonin-permeabilized neutrophils, and the release was blocked by 8Br-cADPR, an antagonist of cADPR. Immunophilin ligands, FK506 and rapamycin, but not cyclosporine A, inhibited cADPR-induced Ca(2+) release. 8Br-cADPR partially reduced fMLP-induced [Ca(2+)](i) rise and abolished the rise in combination with 2APB, an IP(3)-receptor antagonist. Anti-CD38Ab and NADase that interfere with cADPR formation, reduced the fMLP-induced [Ca(2+)](i) rise. When beta-NAD(+), a substrate of ADP-ribosyl cyclase, and cADPR were added to the medium, the former gradually increased [Ca(2+)](i) and the latter potentiated the fMLP-induced [Ca(2+)](i) rise. The beta-NAD(+)-induced [Ca(2+)](i) rise in Ca(2+)-free medium was inhibited by anti-CD38Ab, 8Br-cADPR, FK506, ruthenium red, and thapsigargin. mRNAs of nucleoside transporter (NT), ENT1, ENT2, CNT, and CNT3 were expressed in neutrophils; and their inhibitors, inosine, uridine, and s-(4-nitrobenzyl)-6-thioinosine, reduced the [Ca(2+)](i) rise induced by beta-NAD(+) and fMLP. fMLP-timulated migration was inhibited by the removal of Ca(2+) from the medium or by the addition of 8Br-cADPR, anti-CD38Ab, NADase, and NT inhibitors. These results suggest that cADPR was synthesized extracellularly by CD38, transported into the cells through NTs, and then Ca(2+) was mobilized by FK506-binding protein-dependent process. This process may be involved in fMLP-induced intracellular Ca(2+) signaling and migration in human neutrophils.
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Affiliation(s)
- Katsuya Morita
- Department of Dental Pharmacology, Hiroshima University Graduate School of Biomedical Sciences, Japan
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Abstract
ADP-ribosylation using nicotinamide adenine dinucleotide (NAD+) is an important type of enzymatic reaction that affects many biological processes. A brief introductory review is given here to various ADP-ribosyltransferases, including poly(ADP-ribose) polymerase (PARPs), mono(ADP-ribosyl)-transferases (ARTs), NAD(+)-dependent deacetylases (sirtuins), tRNA 2'-phosphotransferases, and ADP-ribosyl cyclases (CD38 and CD157). Focus is given to the enzymatic reactions, mechanisms, structures, and biological functions.
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Affiliation(s)
- Hening Lin
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
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Billington RA, Travelli C, Ercolano E, Galli U, Roman CB, Grolla AA, Canonico PL, Condorelli F, Genazzani AA. Characterization of NAD uptake in mammalian cells. J Biol Chem 2008; 283:6367-74. [PMID: 18180302 DOI: 10.1074/jbc.m706204200] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Recent evidence has shown that NAD(P) plays a variety of roles in cell-signaling processes. Surprisingly, the presence of NAD(P) utilizing ectoenzymes suggests that NAD(P) is present extracellularly. Indeed, nanomolar concentrations of NAD have been found in plasma and other body fluids. Although very high concentrations of NAD have been shown to enter cells, it is not known whether lower, more physiological concentrations are able to be taken up. Here we show that two mammalian cell types are able to transport low NAD concentrations effectively. Furthermore, extracellular application of NAD was able to counteract FK866-induced cell death and restore intracellular NAD(P) levels. We propose that NAD uptake may play a role in physiological NAD homeostasis.
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Affiliation(s)
- Richard A Billington
- Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche and the Drug and Food Biotechnology Center, Università del Piemonte Orientale, Via Bovio 6, Novara, Italy.
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35
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Churamani D, Boulware MJ, Geach TJ, Martin AC, Moy GW, Su YH, Vacquier VD, Marchant JS, Dale L, Patel S. Molecular characterization of a novel intracellular ADP-ribosyl cyclase. PLoS One 2007; 2:e797. [PMID: 17726527 PMCID: PMC1949048 DOI: 10.1371/journal.pone.0000797] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2007] [Accepted: 08/02/2007] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND ADP-ribosyl cyclases are remarkable enzymes capable of catalyzing multiple reactions including the synthesis of the novel and potent intracellular calcium mobilizing messengers, cyclic ADP-ribose and NAADP. Not all ADP-ribosyl cyclases however have been characterized at the molecular level. Moreover, those that have are located predominately at the outer cell surface and thus away from their cytosolic substrates. METHODOLOGY/PRINCIPAL FINDINGS Here we report the molecular cloning of a novel expanded family of ADP-ribosyl cyclases from the sea urchin, an extensively used model organism for the study of inositol trisphosphate-independent calcium mobilization. We provide evidence that one of the isoforms (SpARC1) is a soluble protein that is targeted exclusively to the endoplasmic reticulum lumen when heterologously expressed. Catalytic activity of the recombinant protein was readily demonstrable in crude cell homogenates, even under conditions where luminal continuity was maintained. CONCLUSIONS/SIGNIFICANCE Our data reveal a new intracellular location for ADP-ribosyl cyclases and suggest that production of calcium mobilizing messengers may be compartmentalized.
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Affiliation(s)
- Dev Churamani
- Department of Physiology, University College London, London, United Kingdom
| | - Michael J. Boulware
- Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
| | - Timothy J. Geach
- Department of Anatomy and Developmental Biology, University College London, London, United Kingdom
| | - Andrew C.R. Martin
- Department of Biochemistry and Molecular Biology, University College London, London, United Kingdom
| | - Gary W. Moy
- Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, California, United States of America
| | - Yi-Hsien Su
- Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, California, United States of America
| | - Victor D. Vacquier
- Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, California, United States of America
| | - Jonathan S. Marchant
- Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
| | - Leslie Dale
- Department of Anatomy and Developmental Biology, University College London, London, United Kingdom
| | - Sandip Patel
- Department of Physiology, University College London, London, United Kingdom
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36
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Govindarajan R, Bakken AH, Hudkins KL, Lai Y, Casado FJ, Pastor-Anglada M, Tse CM, Hayashi J, Unadkat JD. In situ hybridization and immunolocalization of concentrative and equilibrative nucleoside transporters in the human intestine, liver, kidneys, and placenta. Am J Physiol Regul Integr Comp Physiol 2007; 293:R1809-22. [PMID: 17761511 DOI: 10.1152/ajpregu.00293.2007] [Citation(s) in RCA: 112] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
To better understand the role of human equilibrative (hENTs) and concentrative (hCNTs) nucleoside transporters in physiology and pharmacology, we investigated the regional, cellular, and spatial distribution of two hCNTs (hCNT1 and hCNT2) and two hENTs (hENT1 and hENT2) in four human tissues. Using in situ hybridization and immunohistochemical techniques, we found that the duodenum expressed hCNT1 and hCNT2 mRNAs in enterocytes and hENT1 and hENT2 mRNAs in crypt cells. In these cells, the hCNT and hENT proteins were predominantly localized in the apical and lateral membrane, respectively. Hepatocytes expressed higher levels of mRNAs of hENT1, hCNT1, and hENT2 than of hCNT2 and expressed all these proteins at hepatocyte cell borders and in the cytoplasm. While the kidney expressed hCNT1 and hCNT2 mRNAs in the proximal tubules, hENT1 and hENT2 mRNAs were present in the distal tubules, glomeruli, endothelial cells, and vascular smooth muscle cells. Proximal tubules adjacent to corticomedullary junctions expressed hENT1, hCNT1, and hCNT2 mRNA. Immunolocalization studies revealed predominant localization of hCNTs in the brush-border membrane of the proximal tubular epithelial cells and hENTs in the basolateral membrane of the distal tubular epithelial cells. Chorionic villi sections of human term placenta expressed mRNAs and proteins for hENT1 and hENT2 but only mRNA for hCNT2. Immunolocalization studies showed presence of hENT1 in the brush-border membrane of the syncytiotrophoblasts. These data are critical for a better understanding of the role of nucleoside transporters in the physiological and pharmacological effects of nucleosides and nucleoside drugs, respectively.
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Affiliation(s)
- Rajgopal Govindarajan
- Dept. of Pharmaceutics, University of Washington, Box 357610, Seattle, WA 98195, USA
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Zhang J, Visser F, King KM, Baldwin SA, Young JD, Cass CE. The role of nucleoside transporters in cancer chemotherapy with nucleoside drugs. Cancer Metastasis Rev 2007; 26:85-110. [PMID: 17345146 DOI: 10.1007/s10555-007-9044-4] [Citation(s) in RCA: 184] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Nucleoside analogs are important components of treatment regimens for various malignancies. Nucleoside-specific membrane transporters mediate plasma membrane permeation of physiologic nucleosides and most nucleoside analogs, for which the initial event is cellular conversion of nucleosides to active agents. Understanding of the roles of nucleoside transporters in nucleoside drug toxicity and resistance will provide opportunities for potentiating anticancer efficacy and avoiding resistance. Because transportability is a possible determinant of toxicity and resistance of many nucleoside analogs, nucleoside transporter abundance might be a prognostic marker to assess drug resistance. Elucidation of the structural determinants of nucleoside analogs for interaction with transporter proteins as well as the structural features of transporter proteins required for permeant interaction and translocation will lead to "transportability guidelines" for the rational design and therapeutic application of nucleoside analogs as anticancer drugs. It should eventually be possible to develop clinical assays that predict sensitivity and/or resistance to nucleoside anti-cancer drugs and thus to identify those patient populations that will most likely benefit from optimal nucleoside analog treatments. This review discusses recent results from structure/function studies of human nucleoside transporters, the role of nucleoside transport processes in the cytotoxicity and resistance of several anticancer nucleoside analogs and strategies to improve the nucleoside transporter-related anticancer effects of nucleoside analogs.
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Affiliation(s)
- Jing Zhang
- Membrane Protein Research Group, University of Alberta, Edmonton, AB, Canada
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38
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Massullo P, Sumoza-Toledo A, Bhagat H, Partida-Sánchez S. TRPM channels, calcium and redox sensors during innate immune responses. Semin Cell Dev Biol 2006; 17:654-66. [PMID: 17178241 DOI: 10.1016/j.semcdb.2006.11.006] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Melastatin-related TRPM ion channels have emerged as novel therapeutic targets due to their potential ability to modulate the function and fate of immune cells during inflammation, innate, and adaptive immunity. Four family members, TRPM1, TRPM2, TRPM4 and TRPM7 have a strong presence in the immune system. TRPM channels regulate ion-homeostasis by sensing cellular redox status and cytoplasmic calcium levels. TRPM2 for example, is highly expressed in phagocytes. This channel is activated by intracellular ADP-ribose upon exposure to oxidative stress and induces cell death. Here we will review the functional links between TRPM-mediated ion conductance, chemotaxis, apoptosis, and innate immunity.
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Affiliation(s)
- Pam Massullo
- Columbus Children's Research Institute, Center for Microbial Pathogenesis, The Ohio State University, Columbus, OH 43205, USA
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39
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Franco L, Bodrato N, Moreschi I, Usai C, Bruzzone S, Scarf ì S, Zocchi E, De Flora A. Cyclic ADP-ribose is a second messenger in the lipopolysaccharide-stimulated activation of murine N9 microglial cell line. J Neurochem 2006; 99:165-176. [PMID: 16987244 DOI: 10.1111/j.1471-4159.2006.04031.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Lipopolysaccharide, the main component of the cell wall of Gram-negative bacteria, is known to activate microglial cells following its interaction with the CD14/Toll-like receptor complex (TLR-4). The activation pathway triggered by lipopolysaccharide in microglia involves enhanced basal levels of intracellular calcium ([Ca2+]i) and terminates with increased generation of cytokines/chemokines and nitric oxide. Here we demonstrate that in lipopolysaccharide-stimulated murine N9 microglial cells, cyclic ADP-ribose, a universal and potent Ca2+ mobiliser generated from NAD+ by ADP-ribosyl cyclases (ADPRC), behaves as a second messenger in the cell activation pathway. Lipopolysaccharide induced phosphorylation, mediated by multiple protein kinases, of the mammalian ADPRC CD38, which resulted in significantly enhanced ADPRC activity and in a 1.7-fold increase in the concentration of intracellular cyclic ADP-ribose. This event was paralleled by doubling of the basal [Ca2+]i levels, which was largely prevented by the cyclic ADP-ribose antagonists 8-Br-cyclic ADP-ribose and ryanodine (by 75% and 88%, respectively). Both antagonists inhibited, although incompletely, functional events downstream of the lipopolysaccharide-induced microglia-activating pathway, i.e. expression of inducible nitric oxide synthase, overproduction and release of nitric oxide and of tumor necrosis factor alpha. The identification of cyclic ADP-ribose as a key signal metabolite in the complex cascade of events triggered by lipopolysaccharide and eventually leading to enhanced generation of pro-inflammatory molecules may suggest a new therapeutic target for treatment of neurodegenerative diseases related to microglia activation.
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Affiliation(s)
- Luisa Franco
- Department of Experimental Medicine, Section of Biochemistry, and Center of Excellence for Biomedical Research, University of Genova, Genova, Italy
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40
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Liu G, Ding W, Liu X, Mulder KM. c-Fos is required for TGFbeta1 production and the associated paracrine migratory effects of human colon carcinoma cells. Mol Carcinog 2006; 45:582-93. [PMID: 16637060 DOI: 10.1002/mc.20189] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In tumor cells that have lost responsiveness to the growth inhibitory effects of transforming growth factor beta (TGFbeta), increased TGFbeta production by the tumor cells often contributes to cancer progression, primarily through paracrine mechanisms. Here we investigated the major components of the activator protein-1 (AP-1) complex in the TGFbeta1 promoter of human colon carcinoma cells (HCCCs). In contrast to untransformed epithelial cells (UECs), HCCCs displayed constitutive activation of AP-1 at the proximal AP-1 site in the human TGFbeta1 promoter. Further, in contrast to the JunD and Fra-2 components present in the AP-1 complex at this AP-1 site in UECs, c-Fos was the major detectable AP-1 component in HCCCs. Thus, transcriptional factor switching had occurred in HCCCs relative to the UECs, with regard to the proximal AP-1 site of the human TGFbeta1 promoter. Small interfering RNAs (siRNAs) against c-Fos significantly suppressed AP-1 activity at the relevant AP-1 site, and led to a decrease in TGFbeta1 secretion by the HCCCs. Our results indicate for the first time that c-Fos binding at the TGFbeta1 promoter proximal AP-1 site in HCCCs is required for TGFbeta1 production by the tumor cells. Further, we demonstrated that blockade of TGFbeta1 secretion by c-Fos siRNA led to a suppression of the cellular migration and mitogenesis of NIH 3T3 fibroblasts in a paracrine fashion. Thus, c-Fos may have utility as a target for blocking tumor cell-secreted TGFbeta1, thereby suppressing the migratory behavior associated with the malignant phenotype of HCCCs.
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Affiliation(s)
- Guangming Liu
- Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, 17033, USA
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Kirchberger T, Wagner G, Xu J, Cordiglieri C, Wang P, Gasser A, Fliegert R, Bruhn S, Flügel A, Lund FE, Zhang LH, Potter BVL, Guse AH. Cellular effects and metabolic stability of N1-cyclic inosine diphosphoribose and its derivatives. Br J Pharmacol 2006; 149:337-44. [PMID: 16967053 PMCID: PMC1978434 DOI: 10.1038/sj.bjp.0706869] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND AND PURPOSE Recently, a number of mimics of the second messenger cyclic ADP-ribose (cADPR) with replacement of adenosine by inosine were introduced. In addition, various alterations in the molecule ranging from substitutions at C8 of the base up to full replacement of the ribose moieties still retained biological activity. However, nothing is known about the metabolic stability and cellular effects of these novel analogues. EXPERIMENTAL APPROACH cADPR and the inosine-based analogues were incubated with CD38, ADP-ribosyl cyclase and NAD-glycohydrolase and metabolism was analysed by RP-HPLC. Furthermore, the effect of the analogues on cytokine expression and proliferation was investigated in primary T-lymphocytes and T-lymphoma cells. KEY RESULTS Incubation of cADPR with CD38 resulted in degradation to adenosine diphosphoribose. ADP-ribosyl cyclase weakly catabolised cADPR whereas NAD-glycohydrolase showed no such activity. In contrast, N1-cyclic inosine 5'-diphosphoribose (N1-cIDPR) was not hydrolyzed by CD38. Three additional N1-cIDPR analogues showed a similar stability. Proliferation of Jurkat T-lymphoma cells was inhibited by N1-cIDPR, N1-[(phosphoryl-O-ethoxy)-methyl]-N9-[(phosphoryl-O-ethoxy)-methyl]-hypoxanthine-cyclic pyrophosphate (N1-cIDP-DE) and N1-ethoxymethyl-cIDPR (N1-cIDPRE). In contrast, in primary T cells neither proliferation nor cytokine expression was affected by these compounds. CONCLUSIONS AND IMPLICATIONS The metabolic stability of N1-cIDPR and its analogues provides an advantage for the development of novel pharmaceutical compounds interfering with cADPR mediated Ca2+ signalling pathways. The differential effects of N1-cIDPR and N1-cIDPRE on proliferation and cytokine expression in primary T cells versus T-lymphoma cells may constitute a starting point for novel anti-tumor drugs.
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Affiliation(s)
- T Kirchberger
- Centre of Experimental Medicine, Institute of Biochemistry and Molecular Biology I: Cellular Signal Transduction, University Medical Centre Hamburg-Eppendorf Hamburg, Germany
| | - G Wagner
- Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath Bath, UK
| | - J Xu
- National Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Beijing, China
| | - C Cordiglieri
- Department of Neuroimmunology, Max-Planck-Institute for Neurobiology Martinsried, Germany
| | - P Wang
- National Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Beijing, China
| | - A Gasser
- Centre of Experimental Medicine, Institute of Biochemistry and Molecular Biology I: Cellular Signal Transduction, University Medical Centre Hamburg-Eppendorf Hamburg, Germany
| | - R Fliegert
- Centre of Experimental Medicine, Institute of Biochemistry and Molecular Biology I: Cellular Signal Transduction, University Medical Centre Hamburg-Eppendorf Hamburg, Germany
| | - S Bruhn
- Centre of Experimental Medicine, Institute of Biochemistry and Molecular Biology I: Cellular Signal Transduction, University Medical Centre Hamburg-Eppendorf Hamburg, Germany
| | - A Flügel
- Department of Neuroimmunology, Max-Planck-Institute for Neurobiology Martinsried, Germany
| | - F E Lund
- Trudeau Institute Saranac Lake, NY, USA
| | - L-h Zhang
- National Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Beijing, China
| | - B V L Potter
- Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath Bath, UK
| | - A H Guse
- Centre of Experimental Medicine, Institute of Biochemistry and Molecular Biology I: Cellular Signal Transduction, University Medical Centre Hamburg-Eppendorf Hamburg, Germany
- Author for correspondence:
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Young GS, Choleris E, Lund FE, Kirkland JB. Decreased cADPR and increased NAD+ in the Cd38-/- mouse. Biochem Biophys Res Commun 2006; 346:188-92. [PMID: 16750163 DOI: 10.1016/j.bbrc.2006.05.100] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2006] [Accepted: 05/16/2006] [Indexed: 10/24/2022]
Abstract
CD38 is a type II glycoprotein that catalyzes the formation of cyclic ADP-ribose (cADPR), an intracellular calcium signalling molecule, from nicotinamide adenine dinucleotide (NAD(+)). Using a modified version of the fluorimetric cycling assay for cADPR which reduces between-subject variability, we report significant decreases in brain and lung cADPR, which although similar to previously published values, showed much less individual variation. The reduced variation within each group suggests that the range of cADPR is narrower than previously thought, and that the regulatory mechanisms controlling these levels are more finely tuned. We also report significant increases in brain, lung, and kidney NAD(+) in the Cd38(-/-) mouse, and provide the first experimental demonstration of the proximate relationship between CD38 and NAD(+).
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Affiliation(s)
- Genevieve S Young
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ont., Canada N1G 3W1.
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43
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Bezin S, Charpentier G, Fossier P, Cancela JM. The Ca2+-releasing messenger NAADP, a new player in the nervous system. ACTA ACUST UNITED AC 2006; 99:111-8. [PMID: 16458493 DOI: 10.1016/j.jphysparis.2005.12.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Many physiological processes are controlled by a great diversity of Ca2+ signals. Within cell, Ca2+ signals depend upon Ca2+ entry and/or Ca2+ release from internal Ca2+ stores. The control of Ca2+-store mobilization is ensured by a family of messengers comprising inositol 1,4,5 trisphosphate, cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate (NAADP). From recent works, new concepts have emerged where activation of the cells by outside stimuli, acting at the plasma membrane, results in the synthesis of multiple Ca2+-releasing messengers which may interact and shape complex Ca2+ signals in the cytosol as well as in the nucleus. This contribution will cover the most recent advances on NAADP signalling with some emphasis on neurons.
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Affiliation(s)
- Stéphanie Bezin
- Laboratoire de Neurobiologie Cellulaire et Moléculaire, CNRS, UPR 9040, 1 Avenue de La Terrasse, 91198 Gif-sur-Yvette Cedex, France
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Billington RA, Bellomo EA, Floriddia EM, Erriquez J, Distasi C, Genazzani AA. A transport mechanism for NAADP in a rat basophilic cell line. FASEB J 2006; 20:521-3. [PMID: 16403787 DOI: 10.1096/fj.05-5058fje] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
NAADP is a second messenger that releases Ca2+ from intracellular stores. Surprisingly, it has been recently shown that extracellular application of NAADP is capable of inducing intracellular Ca2+ release. This is particularly important since the only mammalian enzymes known to catalyze the synthesis of this second messenger are located extracellularly. In the present manuscript, we have investigated whether mammalian cells possess a transport system capable of transporting this highly charged molecule into cells. Indeed, in RBL-2H3 cells, a rat basophilic cell line, and in SK-N-BE cells, a neuroblastoma cell line, [32P]NAADP is efficiently transported inside cells. NAADP transport is Na+ and Ca2+ dependent, is partially blocked by dipyridamole, but is unaffected by nitrobenzylthioinosine. RBL-2H3 cells also transport [32P]cADPR, but the differences in the pharmacological profile suggest that NAADP transport proceeds by a novel mechanism. Lastly, extracellular application of NAADP, but not NADP, induced a raise in intracellular Ca2+. This is the first demonstration that NAADP is transported into cells and highlights the possibility that, alongside a second messenger, NAADP might also act as an autocrine/paracrine signal.
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Affiliation(s)
- R A Billington
- DiSCAFF and DFB Center, Università del Piemonte Orientale, Novara, Italy.
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Guse AH. Second messenger function and the structure-activity relationship of cyclic adenosine diphosphoribose (cADPR). FEBS J 2005; 272:4590-7. [PMID: 16156781 DOI: 10.1111/j.1742-4658.2005.04863.x] [Citation(s) in RCA: 116] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Cyclic ADP-ribose (cADPR) is a Ca2+ mobilizing second messenger found in various cell types, tissues and organisms. Receptor-mediated formation of cADPR may proceed via transmembrane shuttling of the substrate NAD and involvement of the ectoenzyme CD38, or via so far unidentified ADP-ribosyl cyclases located within the cytosol or in internal membranes. cADPR activates intracellular Ca2+ release via type 2 and 3 ryanodine receptors. The exact molecular mechanism, however, remains to be elucidated. Possibilities are the direct binding of cADPR to the ryanodine receptor or binding via a separate cADPR binding protein. In addition to Ca2+ release, cADPR also evokes Ca2+ entry. The underlying mechanism(s) may comprise activation of capacitative Ca2+ entry and/or activation of the cation channel TRPM2 in conjunction with adenosine diphosphoribose. The development of novel cADPR analogues revealed new insights into the structure-activity relationship. Substitution of either the northern ribose or both the northern and southern ribose resulted in much simpler molecules, which still retained significant biological activity.
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Affiliation(s)
- Andreas H Guse
- University Medical Center Hamburg-Eppendorf, Center of Experimental Medicine, Institute of Biochemistry and Molecular Biology I, Cellular Signal Transduction, Hamburg, Germany.
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Heidemann AC, Schipke CG, Kettenmann H. Extracellular application of nicotinic acid adenine dinucleotide phosphate induces Ca2+ signaling in astrocytes in situ. J Biol Chem 2005; 280:35630-40. [PMID: 16061474 DOI: 10.1074/jbc.m507338200] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Nicotinic acid adenine dinucleotide phosphate (NAADP+) has been identified as a novel second messenger triggering Ca2+ release from intracellular stores. Here we report that murine cortical astrocytes in culture and in acute slices respond with transient intracellular Ca2+ increases to extracellularly applied NAADP+ and express the NAADP+-producing enzyme CD38. The Ca2+ transients triggered by NAADP+ occurred with an average delay of 35 s as compared with ATP-triggered Ca2+ signaling, suggesting that NAADP+ may have to enter the cell to act. Blockage of connexin hemichannels (a possible entry route for NAADP+ into the cell) reduced the number of astrocytes responding to NAADP+. Disruption of lysosomes as the suggested site of NAADP+ receptors reduced the number of astrocytes responding to NAADP+ strongly. The NAADP+-triggered Ca2+ signal also depended on intact endoplasmic reticulum Ca2+ stores linked to activation of inositol 1,4,5-trisphosphate receptors and on the activity of voltage-gated Ca2+ channels. Adenosine receptor-mediated signaling contributes to the NAADP+-evoked signal, since it is strongly reduced by the adenosine receptor blocker CGS-15943. Moreover, NAADP+ triggered responses in all other cell types (cultured cerebellar neurons, microglia, and oligodendrocytes) of the central nervous system.
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Affiliation(s)
- Antje C Heidemann
- Max-Delbrück-Center for Molecular Medicine, Cellular Neuroscience, 10 Robert-Rössle-Strasse, Berlin D-13092, Germany
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Deshpande DA, White TA, Dogan S, Walseth TF, Panettieri RA, Kannan MS. CD38/cyclic ADP-ribose signaling: role in the regulation of calcium homeostasis in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 2005; 288:L773-88. [PMID: 15821018 DOI: 10.1152/ajplung.00217.2004] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The contractility of airway smooth muscle cells is dependent on dynamic changes in the concentration of intracellular calcium. Signaling molecules such as inositol 1,4,5-trisphosphate and cyclic ADP-ribose play pivotal roles in the control of intracellular calcium concentration. Alterations in the processes involved in the regulation of intracellular calcium concentration contribute to the pathogenesis of airway diseases such as asthma. Recent studies have identified cyclic ADP-ribose as a calcium-mobilizing second messenger in airway smooth muscle cells, and modulation of the pathway involved in its metabolism results in altered calcium homeostasis and may contribute to airway hyperresponsiveness. In this review, we describe the basic mechanisms underlying the dynamics of calcium regulation and the role of CD38/cADPR, a novel pathway, in the context of airway smooth muscle function and its contribution to airway diseases such as asthma.
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Affiliation(s)
- Deepak A Deshpande
- Dept. of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA
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Huang M, Wang Y, Mitchell BS, Graves LM. Regulation of equilibrative nucleoside uptake by protein kinase inhibitors. NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 2005; 23:1445-50. [PMID: 15571274 DOI: 10.1081/ncn-200027667] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
The uptake of nucleosides and nucleoside analogs into human leukemia K562 cells is facilitated by the equilibrative transporters ENT1 and ENT2. Incubation of K562 cells with a variety of protein kinase inhibitors inhibited the transport of both uridine (ARA-C) and cytidine (CPEC) analogs. These inhibitory effects were observed for a large number of kinase inhibitors including those against p38 MAPK, the EGF receptor kinase, protein kinase C, TOR and others. Thus these results suggest that the nucleoside transporters are unexpected targets for kinase inhibitors and may influence the design and application of combinatorial approaches of nucleoside analogs and kinase inhibitors in clinical applications.
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Affiliation(s)
- Min Huang
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Bai N, Lee HC, Laher I. Emerging role of cyclic ADP-ribose (cADPR) in smooth muscle. Pharmacol Ther 2004; 105:189-207. [PMID: 15670626 DOI: 10.1016/j.pharmthera.2004.10.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2004] [Accepted: 10/14/2004] [Indexed: 10/26/2022]
Abstract
Cyclic adenosine diphosphate ribose (cADPR) is a naturally occurring cyclic nucleotide and represents a novel class of endogenous Ca(2+) messengers implicated in the regulation of the gating properties of ryanodine receptors (RyRs). This action of cADPR occurs independently from the inositol-1,4,5-trisphosphate (IP(3)) receptor. The regulation of intracellular Ca(2+) release is a fundamental element of cellular Ca(2+) homeostasis since a number of smooth muscle functions (tone, proliferation, apoptosis, and gene expression) are modulated by intracellular Ca(2+) concentration ([Ca(2+)](i)). There has been a surge in the efforts aimed at understanding the mechanisms of cADPR-mediated Ca(2+) mobilization and its impact on smooth muscle function. This review summarizes the proposed roles of cADPR in the regulation of smooth muscle tone.
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Affiliation(s)
- Ni Bai
- Department of Pharmacology and Therapeutics, University of British Columbia Vancouver, BC, Canada V6T 1Z3
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Podestà M, Benvenuto F, Pitto A, Figari O, Bacigalupo A, Bruzzone S, Guida L, Franco L, Paleari L, Bodrato N, Usai C, De Flora A, Zocchi E. Concentrative uptake of cyclic ADP-ribose generated by BST-1+ stroma stimulates proliferation of human hematopoietic progenitors. J Biol Chem 2004; 280:5343-9. [PMID: 15574424 DOI: 10.1074/jbc.m408085200] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Cyclic ADP-ribose (cADPR) is an intracellular calcium mobilizer generated from NAD(+) by the ADP-ribosyl cyclases CD38 and BST-1. cADPR, both exogenously added and paracrinally produced by a CD38(+) feeder layer, has recently been demonstrated to stimulate the in vitro proliferation of human hemopoietic progenitors (HP) and also the in vivo expansion of hemopoietic stem cells. The low density of BST-1 expression on bone marrow (BM) stromal cells and the low specific activity of the enzyme made it unclear whether cADPR generation by a BST-1(+) stroma could stimulate HP proliferation in the BM microenvironment. We developed and characterized two BST-1(+) stromal cell lines, expressing an ectocellular cyclase activity similar to that of BST-1(+) human mesenchymal stem cells, the precursors of BM stromal cells. Long term co-culture of cord blood-derived HP over these BST-1(+) feeders determined their expansion. Influx of paracrinally generated cADPR into clonogenic HP was mediated by a concentrative, nitrobenzylthioinosine- and dipyridamole-inhibitable nucleoside transporter, this providing a possible explanation to the effectiveness of the hormone-like concentrations of the cyclic nucleotide measured in the medium conditioned by BST-1(+) feeders. These results suggest that the BST-1-catalyzed generation of extracellular cADPR, followed by the concentrative uptake of the cyclic nucleotide by HP, may be physiologically relevant in normal hemopoiesis.
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Affiliation(s)
- Marina Podestà
- Department of Hematology, 2nd Division, Pad.5, S. Martino Hospital, Largo R. Benzi 10, 16132 Genova, Italy
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