RESUMEN
Herein proteomic profiling of the rat hippocampus from the kindling and pilocarpine models of epilepsy was performed to achieve new potential targets for treating epileptic seizures. A total of 144 differently expressed proteins in both left and right hippocampi by two-dimensional electrophoresis coupled to matrix-assisted laser desorption-mass spectrometry were identified across the rat models of epilepsy. Based on network analysis, the majority of differentially expressed proteins were associated with Ca2+ homeostasis. Changes in ADP-ribosyl cyclase (ADPRC), lysophosphatidic acid receptor 3 (LPAR3), calreticulin, ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), synaptosomal nerve-associated protein 25 (SNAP 25) and transgelin 3 proteins were probed by Western blot analysis and validated using immunohistochemistry. Inhibition of calcium influx by 8-Bromo-cADP-Ribose (8-Br-cADPR) and 2-Aminoethyl diphenylborinate (2-APB) which act via the ADPRC and LPAR3, respectively, attenuated epileptic seizures. Considering a wide range of molecular events and effective role of calcium homeostasis in epilepsy, polypharmacy with multiple realistic targets should be further explored to reach the most effective treatments.
Asunto(s)
Calcio/metabolismo , Epilepsia/genética , Epilepsia/metabolismo , Hipocampo/metabolismo , Excitación Neurológica , Pilocarpina , Proteómica , ADP-Ribosil Ciclasa/metabolismo , Animales , ADP-Ribosa Cíclica/análogos & derivados , ADP-Ribosa Cíclica/fisiología , Modelos Animales de Enfermedad , Electroforesis/métodos , Epilepsia/terapia , Homeostasis , Masculino , Terapia Molecular Dirigida , Ratas Wistar , Receptores del Ácido Lisofosfatídico/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Proteína 25 Asociada a Sinaptosomas/metabolismoRESUMEN
Nicotinamide adenine dinucleotide (NAD) has been known since a long period of time as co-factor of oxidoreductases. However, in the past couple of decades further roles have been assigned to NAD. Here, metabolism of NAD to the Ca²âº mobilizing second messengers cyclic adenosine diphosphoribose, nicotinic acid adenine dinucleotide phosphate and adenosine diphosphoribose is reviewed. Moreover, the mechanisms of Ca²âº mobilization by these adenine nucleotides and their putative target Ca²âº channels, ryanodine receptors and transient receptor potential channels are discussed. This article is part of a Special Issue entitled: Cofactor-dependent proteins: evolution, chemical diversity and bio-applications.
Asunto(s)
Calcio/metabolismo , NAD/fisiología , Sistemas de Mensajero Secundario/fisiología , Adenosina Difosfato Ribosa/fisiología , Animales , ADP-Ribosa Cíclica/fisiología , Humanos , NADP/análogos & derivados , NADP/fisiologíaRESUMEN
Recent research suggests that in addition to their role as soluble electron carriers, pyridine nucleotides [NAD(P)(H)] also regulate ion transport mechanisms. This mode of regulation seems to have been conserved through evolution. Several bacterial ion-transporting proteins or their auxiliary subunits possess nucleotide-binding domains. In eukaryotes, the Kv1 and Kv4 channels interact with pyridine nucleotide-binding ß-subunits that belong to the aldo-keto reductase superfamily. Binding of NADP(+) to Kvß removes N-type inactivation of Kv currents, whereas NADPH stabilizes channel inactivation. Pyridine nucleotides also regulate Slo channels by interacting with their cytosolic regulator of potassium conductance domains that show high sequence homology to the bacterial TrkA family of K(+) transporters. These nucleotides also have been shown to modify the activity of the plasma membrane K(ATP) channels, the cystic fibrosis transmembrane conductance regulator, the transient receptor potential M2 channel, and the intracellular ryanodine receptor calcium release channels. In addition, pyridine nucleotides also modulate the voltage-gated sodium channel by supporting the activity of its ancillary subunit-the glycerol-3-phosphate dehydrogenase-like protein. Moreover, the NADP(+) metabolite, NAADP(+), regulates intracellular calcium homeostasis via the 2-pore channel, ryanodine receptor, or transient receptor potential M2 channels. Regulation of ion channels by pyridine nucleotides may be required for integrating cell ion transport to energetics and for sensing oxygen levels or metabolite availability. This mechanism also may be an important component of hypoxic pulmonary vasoconstriction, memory, and circadian rhythms, and disruption of this regulatory axis may be linked to dysregulation of calcium homeostasis and cardiac arrhythmias.
Asunto(s)
Cationes/metabolismo , Canales Iónicos/fisiología , Transporte Iónico/fisiología , NADP/fisiología , NAD/fisiología , Animales , Sitios de Unión , Señalización del Calcio/fisiología , Proteínas Portadoras/fisiología , ADP-Ribosa Cíclica/fisiología , Células Eucariotas/metabolismo , Homeostasis/fisiología , Humanos , Activación del Canal Iónico/fisiología , Canales Iónicos/química , Mamíferos/metabolismo , NADP/análogos & derivados , Fosforilación , Potasio/metabolismo , Células Procariotas/metabolismo , Sodio/metabolismoRESUMEN
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.
Asunto(s)
Calcio/metabolismo , ADP-Ribosa Cíclica/fisiología , NADP/análogos & derivados , Páncreas/metabolismo , ADP-Ribosil Ciclasa 1/metabolismo , Animales , ADP-Ribosa Cíclica/metabolismo , Retículo Endoplásmico/metabolismo , Humanos , Lisosomas/metabolismo , Modelos Biológicos , NADP/metabolismo , NADP/fisiología , Páncreas/citología , Sistemas de Mensajero Secundario/fisiologíaRESUMEN
Ca(2+) signals are probably the most common intracellular signaling elements, controlling an extensive range of responses in virtually all cells. Many cellular stimuli, often acting at cell surface receptors, evoke Ca(2+) signals by mobilizing Ca(2+) from intracellular stores. Inositol trisphosphate (IP3) was the first messenger shown to link events at the plasma membrane to release of Ca(2+) from the endoplasmic reticulum (ER), through activation of IP3-gated Ca(2+) release channels (IP3 receptors). Subsequently, two additional Ca(2+) mobilizing messengers were discovered, cADPR and NAADP. Both are metabolites of pyridine nucleotides, and may be produced by the same class of enzymes, ADP-ribosyl cyclases, such as CD38. Whilst cADPR mobilizes Ca(2+) from the ER by activation of ryanodine receptors (RyRs), NAADP releases Ca(2+) from acidic stores by a mechanism involving the activation of two pore channels (TPCs).
Asunto(s)
Calcio/metabolismo , ADP-Ribosa Cíclica/fisiología , NADP/análogos & derivados , Animales , Señalización del Calcio , Humanos , NADP/fisiologíaRESUMEN
It was first proposed that cyclic ADP-ribose (cADPR) could activate ryanodine receptors (RyR) in 1991. Following a subsequent report that cADPR could activate cardiac RyR (RyR2) reconstituted into artificial membranes and stimulate Ca(2+) -release from isolated cardiac SR, there has been a steadily mounting stockpile of publications proclaiming the physiological and pathophysiological importance of cADPR in the cardiovascular system. It was only 2 years earlier, in 1989, that cADPR was first identified as the active metabolite of nicotinamide adenine dinucleotide (NAD), responsible for triggering the release of Ca(2+) from crude homogenates of sea urchin eggs. Twenty years later, can we boast of being any closer to unraveling the mechanisms by which cADPR modulates intracellular Ca(2+) -release? This review sets out to examine the mechanisms underlying the effects of cADPR and ask whether cADPR is an important signaling molecule in the heart.
Asunto(s)
ADP-Ribosa Cíclica/fisiología , Corazón/fisiología , Óvulo/fisiología , Canal Liberador de Calcio Receptor de Rianodina/fisiología , Erizos de Mar/fisiología , Animales , Señalización del Calcio/fisiología , ADP-Ribosa Cíclica/metabolismo , Fertilización , Humanos , NADP/análogos & derivados , NADP/metabolismo , Unión Proteica , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Proteínas de Unión a Tacrolimus/fisiologíaRESUMEN
Understanding of calcium signaling pathways in cells is essential for elucidating the mechanisms of both normal cell function and cancer development. Calcium messengers play the crucial role for intracellular Ca(2+) release. We propose a new approach to detecting the calcium second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) in cell extracts using surface-enhanced Raman spectroscopy (SERS). Currently available radioreceptor binding and enzymatic assays require extensive sample preparation and take more than 12 h. With a SERS sensor, NAADP can be detected in less than 1 min without any special sample preparation. To the best of our knowledge, this is the first demonstration of using SERS for calcium signaling applications.
Asunto(s)
Señalización del Calcio , Calcio/metabolismo , NADP/análogos & derivados , Espectrometría Raman/métodos , Línea Celular Tumoral , ADP-Ribosa Cíclica/química , ADP-Ribosa Cíclica/fisiología , Oro/química , Humanos , Inositol 1,4,5-Trifosfato/química , Inositol 1,4,5-Trifosfato/fisiología , Nanopartículas del Metal/química , NADP/análisis , NADP/química , NADP/fisiología , Sistemas de Mensajero SecundarioRESUMEN
Oxytocin is important for regulating a number of physiological processes. Disruption of the secretion, metabolism or action of oxytocin results in an impairment of reproductive function, social and sexual behaviours, and stress responses. This review discusses current views on the regulation and autoregulation of oxytocin release in the hypothalamic-neurohypophysial system, with special focus on the activity of the CD38/cADP-ribose system as a new component in this regulation. Data from our laboratories indicate that an impairment of this system results in alterations of oxytocin secretion and abnormal social behaviour, thus suggesting new clues that help in our understanding of the pathogenesis of neurodevelopmental disorders.
Asunto(s)
ADP-Ribosil Ciclasa 1/fisiología , ADP-Ribosa Cíclica/fisiología , Oxitocina/metabolismo , Conducta Social , Animales , Hipotálamo/metabolismo , Ratones , Ratones NoqueadosRESUMEN
Insulin has an autocrine/paracrine role through insulin receptors in pancreatic ß-cells. Herein, we show the insulin receptor signaling pathway underlying CD38/ADPR-cyclase activation for NAADP/cADPR formation to induce Ca2+ rise, ultimately resulting in ß-cell proliferation. Binding of insulin on insulin receptors leads to the activation of IRS/Akt/PI3K/PLC. Activation of PLC generates IP3 and DAG; the former induces Ca (2+) release, resulting in activation of CD38/ADPR-cyclase for cADPR production via cGMP-dependent mechanism and the latter activates PKC, resulting in activation of ADPR-cyclase for NAADP synthesis. The NAADP-induced Ca (2+) signal is required for IP3-induced Ca (2+) release from the ER. CD38 plays an important role in insulin receptor signaling in ß-cells by reflecting a declined sustained Ca (2+) signal, cADPR levels, and ß-cell proliferation in response to insulin in CD38 (-/-) islets. However, evidence indicates that a hitherto-unidentified ADPR cyclase in addition to CD38 participates in insulin-induced signaling through cADPR and NAADP synthesis. In conclusion, insulin receptor signaling in ß-cells employs three Ca (2+) signaling messengers, IP3, NAADP, and cADPR through a complex but concerted action of signaling molecules for Ca2+ signaling, which is involved in the proliferation of the islets.
Asunto(s)
Proliferación Celular , ADP-Ribosa Cíclica/fisiología , Fosfatos de Inositol/fisiología , Células Secretoras de Insulina/fisiología , NADP/análogos & derivados , Receptor de Insulina/metabolismo , ADP-Ribosil Ciclasa 1/genética , ADP-Ribosil Ciclasa 1/metabolismo , Animales , Calcio/metabolismo , Calcio/fisiología , Señalización del Calcio/genética , Señalización del Calcio/fisiología , Células Cultivadas , ADP-Ribosa Cíclica/metabolismo , Fosfatos de Inositol/metabolismo , Células Secretoras de Insulina/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , NADP/metabolismo , NADP/fisiología , Receptor de Insulina/fisiología , Sistemas de Mensajero Secundario/fisiología , Transducción de Señal/genética , Transducción de Señal/fisiologíaRESUMEN
The body of literature characterizing cyclic adenosine diphosphoribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) as Ca2+-mobilizing second messengers is growing apace. However, their unique properties may, for the uninitiated, make them difficult to work with. This article reviews many of the available techniques (and associated pitfalls) for investigating these nucleotide messengers, predominantly focusing upon optical techniques using fluorescent reporters to measure Ca2+ in the cytosol as well as Ca2+ or pH within the lumen of intracellular organelles.
Asunto(s)
Calcio/metabolismo , ADP-Ribosa Cíclica/fisiología , NADP/análogos & derivados , Sistemas de Mensajero Secundario/fisiología , Animales , Concentración de Iones de Hidrógeno , NADP/fisiología , Orgánulos/metabolismo , Óvulo , Permeabilidad/efectos de los fármacos , Erizos de MarRESUMEN
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.
Asunto(s)
ADP-Ribosil Ciclasa/fisiología , Ácido Abscísico/fisiología , Calcio/metabolismo , Proliferación Celular , Células Madre Mesenquimatosas/fisiología , Reguladores del Crecimiento de las Plantas/fisiología , Ácido Abscísico/farmacología , Diferenciación Celular , Proliferación Celular/efectos de los fármacos , Células Cultivadas , ADP-Ribosa Cíclica/fisiología , Ciclooxigenasa 2/metabolismo , Citocinas/biosíntesis , Dinoprostona/metabolismo , Activación Enzimática , Humanos , Células Madre Mesenquimatosas/citología , Reguladores del Crecimiento de las Plantas/farmacología , Sistemas de Mensajero Secundario/fisiología , Transducción de Señal/fisiologíaRESUMEN
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.
Asunto(s)
ADP-Ribosil Ciclasa 1/fisiología , Complejo SIDA Demencia/patología , Astrocitos/patología , Señalización del Calcio/fisiología , ADP-Ribosa Cíclica/fisiología , VIH-1/fisiología , Mediadores de Inflamación/fisiología , ADP-Ribosil Ciclasa 1/genética , Complejo SIDA Demencia/genética , Complejo SIDA Demencia/metabolismo , Astrocitos/metabolismo , Células Cultivadas , ADP-Ribosa Cíclica/genética , Feto , Proteína gp120 de Envoltorio del VIH/fisiología , Humanos , Líquido Intracelular/metabolismo , Neuronas/metabolismo , Neuronas/patologíaRESUMEN
Cyclic adenosine diphosphoribose (cADPR) is an endogenous Ca2+-mobilizing second messenger found in cells of animals, plants, and protozoans. It is formed by a specific class of enzymes, the ADP-ribosyl cyclases. cADPR stimulates Ca2+ release by means of ryanodine receptors located in the sarcoplasmic and endoplasmic reticulum. Recently, a role for cADPR has been demonstrated in the obligate intracellular protozoan pathogen Toxoplasma gondii. In T. gondii, stress conditions evoked synthesis of the plant hormone abscisic acid by the apicoplast, a remnant organelle of an algal endosymbiont of T. gondii. Abscisic acid in turn activated formation of cADPR within T. gondii, resulting in Ca2+ release and secretion of proteins involved in egress of T. gondii from its host cell. Evidence for a synthetic pathway of plant origin was obtained with the ABA synthesis inhibitor fluridone, which antagonized cellular egress and induced differentiation of long-lived semidormant cystic forms of T. gondii. Moreover, fluridone protected mice from toxoplasmosis.
Asunto(s)
Señalización del Calcio , Calcio/metabolismo , ADP-Ribosa Cíclica/fisiología , Regulación de la Expresión Génica , Toxoplasma/metabolismo , Animales , ADP-Ribosa Cíclica/metabolismo , Proteínas de Unión al GTP/metabolismo , Ratones , Modelos Biológicos , Fosforilación , Sistemas de Mensajero Secundario , Transducción de Señal , Simbiosis , Toxoplasma/patogenicidadRESUMEN
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.
Asunto(s)
Calcio/metabolismo , ADP-Ribosa Cíclica/fisiología , N-Formilmetionina Leucil-Fenilalanina/farmacología , Neutrófilos/fisiología , ADP-Ribosil Ciclasa 1/fisiología , Movimiento Celular , ADP-Ribosa Cíclica/análogos & derivados , ADP-Ribosa Cíclica/farmacología , Humanos , Proteínas de Transporte de Nucleósidos/fisiología , Proteínas de Unión a Tacrolimus/fisiologíaRESUMEN
Contractility of airway smooth muscle requires elevation of intracellular calcium concentration. Under resting conditions, airway smooth muscle cells maintain a relatively low intracellular calcium concentration, and activation of the surface receptors by contractile agonists results in an elevation of intracellular calcium, culminating in contraction of the cell. The pattern of elevation of intracellular calcium brought about by agonists is a dynamic process and involves the coordinated activities of ion channels located in the plasma membrane and the sarcoplasmic reticulum. Among the signaling molecules involved in this dynamic calcium regulation in airway smooth muscle cells are inositol 1,4,5-trisphosphate and cyclic ADP-ribose, which mobilize calcium from the sarcoplasmic reticulum by acting via the inositol 1,4,5-trisphosphate and ryanodine receptors, respectively. In addition, calcium influx from the extracellular space is critical for the repletion of the intracellular calcium stores during activation of the cells by agonists. Calcium influx can occur via voltage- and receptor-gated channels in the plasma membrane, as well as by influx that is triggered by depletion of the intracellular stores (i.e., store-operated calcium entry mechanism). Transient receptor potential proteins appear to mediate the calcium influx via receptor- and store-operated channels. Recent studies have shown that proinflammatory cytokines regulate the expression and activity of the pathways involved in intracellular calcium regulation, thereby contributing to airway smooth muscle cell hyperresponsiveness. In this review, we will discuss the specific roles of cyclic ADP-ribose/ryanodine receptor channels and transient receptor potential channels in the regulation of intracellular calcium in airway smooth muscle cells.
Asunto(s)
Señalización del Calcio/fisiología , Músculo Liso/metabolismo , ADP-Ribosil Ciclasa , ADP-Ribosil Ciclasa 1/fisiología , Animales , ADP-Ribosa Cíclica/fisiología , Citocinas/fisiología , Espacio Extracelular/metabolismo , Humanos , Inositol 1,4,5-Trifosfato/fisiología , Potenciales de la Membrana , Contracción Muscular/fisiología , Retículo Sarcoplasmático/metabolismoRESUMEN
The review considers Ca2+ -messenger systems in primitive multicellulars (sponges and hydrozoa organisms). Analysis is performed of Ca2+ participation in regulation of early development of the organisms, their mobility, metamorphosis, chemoreception, and some other functions.
Asunto(s)
Evolución Biológica , Señalización del Calcio , Hidrozoos/fisiología , Poríferos/fisiología , Animales , Comunicación Celular/fisiología , Movimiento Celular/fisiología , ADP-Ribosa Cíclica/fisiología , Hidrozoos/citología , Poríferos/citologíaRESUMEN
Nicotinamide adenine dinucleotide (NAD(+)) has crucial roles in many cellular processes, both as a coenzyme for redox reactions and as a substrate to donate ADP-ribose units. Enzymes involved in NAD(+) metabolism are attractive targets for drug discovery against a variety of human diseases, including cancer, multiple sclerosis, neurodegeneration and Huntington's disease. A small-molecule inhibitor of nicotinamide phosphoribosyltransferase, an enzyme in the salvage pathway of NAD(+) biosynthesis, is presently in clinical trials against cancer. An analog of a kynurenine pathway intermediate is efficacious against multiple sclerosis in an animal model. Indoleamine 2,3-dioxygenase plays an important role in immune evasion by cancer cells and other disease processes. Inhibitors against kynurenine 3-hydroxylase can reduce the production of neurotoxic metabolites while increasing the production of neuroprotective compounds. This review summarizes the existing knowledge on NAD(+) metabolic enzymes, with emphasis on their relevance for drug discovery.
Asunto(s)
Diseño de Fármacos , NAD/metabolismo , Acrilamidas/farmacología , Acrilamidas/uso terapéutico , Adenosina Difosfato Ribosa/metabolismo , Envejecimiento/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/metabolismo , Ensayos Clínicos Fase II como Asunto , ADP-Ribosa Cíclica/fisiología , Daño del ADN , Inhibidores Enzimáticos/farmacología , Humanos , Quinurenina/metabolismo , Ratones , NAD/fisiología , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Piperidinas/farmacología , Piperidinas/uso terapéutico , Poli Adenosina Difosfato Ribosa/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Sirtuinas/antagonistas & inhibidores , Sirtuinas/metabolismo , Triptófano/metabolismoRESUMEN
PURPOSE: Calcium ions play a pivotal role in phototransduction. In this study, the presence and functional role of the adenosine diphosphoribosyl (ADPR)-cyclase-cyclic ADP-ribose (cADPR) system in bovine retinal rod outer segments (ROS) was investigated. METHODS: A Ca(2+) release from osmotically intact ROS discs elicited by cADPR was studied in the presence of the Ca(2+) tracer fluo-3. Endogenous cyclic guanosine diphosphate ribose (cGDPR) formation in discs was investigated by spectrophotometric detection of its synthesis from nicotinamide guanine dinucleotide (NGD(+)). ADPR-cyclase was also investigated at a structural level on mildly denaturing SDS-PAGE by production of cyclic inosine diphosphate ribose from nicotinamide hypoxantine dinucleotide (NHD(+)). Western immunoblot analysis with a specific antibody was conducted to verify the presence of ryanodine-sensitive Ca(2+) channels (RyRs) in ROS discs. RESULTS: cADPR-dependent Ca(2+) release was a linear function of extravesicular free Ca(2+) concentration, between 200 and 900 nM Ca(2+). When free Ca(2+) was 203 +/- 10 nM the mean Ca(2+) release was 23 +/- 3 pmol/mL per milligram protein. The average rate of cGDPR production was 13 +/- 2 nmol cGDPR/min per milligram protein, by a putative enzyme with an apparent molecular mass of 53 +/- 1 kDa. ROS ADPR-cyclase was localized in the membranous fraction. No nicotinamide adenine dinucleotide glycohydrolase (NADase) activity was detected. The presence of RyR channels in pure disc preparations was confirmed by confocal laser scanning microscopy. CONCLUSIONS: A cADPR metabolism may be present in retinal ROS discs, which may be Ca(2+) stores operated by cADPR. A model is proposed for the physiological role of cADPR-mediated Ca(2+) release in bovine ROS.
Asunto(s)
ADP-Ribosil Ciclasa/fisiología , Señalización del Calcio/fisiología , Calcio/metabolismo , ADP-Ribosa Cíclica/fisiología , Segmento Externo de la Célula en Bastón/enzimología , Animales , Western Blotting , Canales de Calcio/metabolismo , Bovinos , Electroforesis en Gel de Poliacrilamida , Azúcares de Guanosina Difosfato/metabolismo , Nucleótidos de Inosina/metabolismo , Microscopía Confocal , NAD+ Nucleosidasa/metabolismo , Rodopsina/metabolismo , Segmento Externo de la Célula en Bastón/ultraestructura , Espectrofotometría Atómica , Visión OcularAsunto(s)
ADP-Ribosil Ciclasa 1/inmunología , Señalización del Calcio/fisiología , Quimiotaxis/fisiología , ADP-Ribosa Cíclica/biosíntesis , Inmunidad Innata , Glicoproteínas de Membrana/inmunología , NAD/metabolismo , ADP-Ribosil Ciclasa 1/antagonistas & inhibidores , ADP-Ribosil Ciclasa 1/deficiencia , ADP-Ribosil Ciclasa 1/genética , Animales , Bacteriemia/inmunología , Quimiocinas/fisiología , ADP-Ribosa Cíclica/antagonistas & inhibidores , ADP-Ribosa Cíclica/fisiología , Células Dendríticas/citología , Células Dendríticas/inmunología , Líquido Extracelular/metabolismo , Humanos , Inmunización , Infecciones/inmunología , Inflamación/inmunología , Pulmón/inmunología , Pulmón/microbiología , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Ratones , Ratones Noqueados , Ratones Transgénicos , Modelos Inmunológicos , Neutrófilos/fisiología , Neumonía Neumocócica/inmunología , Receptores de Quimiocina/fisiología , Especificidad por Sustrato , Subgrupos de Linfocitos T/inmunologíaRESUMEN
In smooth muscle, Ca(2+) controls diverse activities including cell division, contraction and cell death. Of particular significance in enabling Ca(2+) to perform these multiple functions is the cell's ability to localize Ca(2+) signals to certain regions by creating high local concentrations of Ca(2+) (microdomains), which differ from the cytoplasmic average. Microdomains arise from Ca(2+) influx across the plasma membrane or release from the sarcoplasmic reticulum (SR) Ca(2+) store. A single Ca(2+) channel can create a microdomain of several micromolar near (approximately 200 nm) the channel. This concentration declines quickly with peak rates of several thousand micromolar per second when influx ends. The high [Ca(2+)] and the rapid rates of decline target Ca(2+) signals to effectors in the microdomain with rapid kinetics and enable the selective activation of cellular processes. Several elements within the cell combine to enable microdomains to develop. These include the brief open time of ion channels, localization of Ca(2+) by buffering, the clustering of ion channels to certain regions of the cell and the presence of membrane barriers, which restrict the free diffusion of Ca(2+). In this review, the generation of microdomains arising from Ca(2+) influx across the plasma membrane and the release of the ion from the SR Ca(2+) store will be discussed and the contribution of mitochondria and the Golgi apparatus as well as endogenous modulators (e.g. cADPR and channel binding proteins) will be considered.