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1.
Biochim Biophys Acta ; 1854(9): 1132-7, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25534250

ABSTRACT

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 Ca²âº mobilizing second messengers cyclic adenosine diphosphoribose, nicotinic acid adenine dinucleotide phosphate and adenosine diphosphoribose is reviewed. Moreover, the mechanisms of Ca²âº mobilization by these adenine nucleotides and their putative target Ca²âº 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.


Subject(s)
Calcium/metabolism , NAD/physiology , Second Messenger Systems/physiology , Adenosine Diphosphate Ribose/physiology , Animals , Cyclic ADP-Ribose/physiology , Humans , NADP/analogs & derivatives , NADP/physiology
3.
J Physiol ; 590(5): 1121-38, 2012 Mar 01.
Article in English | MEDLINE | ID: mdl-22219339

ABSTRACT

Hypertonicity-induced cation channels (HICCs) are key-players in proliferation and apoptosis but their molecular correlate remains obscure. Furthermore, the activation profile of HICCs is not well defined yet. We report here that, in HeLa cells, intracellular adenosine diphosphate ribose (ADPr) and cyclic ADPr (cADPr), as supposed activators of TRPM2, elicited cation currents that were virtually identical to the osmotic activation of HICCs. Silencing of the expression of TRPM2 and of the ecto-enzyme CD38 (as a likely source of ADPr and cADPr) inhibited HICC as well as nucleotide-induced currents and, in parallel, the hypertonic volume response of cells (the regulatory volume increase, RVI) was attenuated. Quantification of intracellular cADPr levels and the systematic application of extra- vs. intracellular nucleotides indicate that the outwardly directed gradient rather than the cellular activity of ADPr and cADPr triggers TRPM2 activation, probably along with a simultaneous biotransformation of nucleotides.Cloning of TRPM2 identified the ΔC-splice variant as the molecular correlate of the HICC, which could be strongly supported by a direct comparison of the respective Ca²âº selectivity. Finally, immunoprecipitation and high-resolution FRET/FLIM imaging revealed the interaction of TRPM2 and CD38 in the native as well as in a heterologous (HEK293T) expression system. We propose transport-related nucleotide export via CD38 as a novel mechanism of TRPM2/HICC activation. With the biotransformation of nucleotides running in parallel, continuous zero trans-conditions are achieved which will render the system infinitely sensitive.


Subject(s)
ADP-ribosyl Cyclase 1/physiology , Adenosine Diphosphate Ribose/physiology , Membrane Glycoproteins/physiology , TRPM Cation Channels/physiology , Cell Proliferation , Gene Silencing , HEK293 Cells , HeLa Cells , Humans , NAD/physiology , Protein Isoforms , RNA, Small Interfering/genetics , Reactive Oxygen Species/metabolism
5.
Structure ; 17(7): 939-51, 2009 Jul 15.
Article in English | MEDLINE | ID: mdl-19604474

ABSTRACT

Besides its function as an essential redox cofactor, nicotinamide adenine dinucleotide (NAD) also serves as a consumable substrate for several reactions with broad impact on many cellular processes. NAD homeostasis appears to be tightly controlled, but the mechanism of its regulation is little understood. Here we demonstrate that a previously predicted bacterial transcriptional regulator, NrtR, represses the transcription of NAD biosynthetic genes in vitro. The NAD metabolite ADP-ribose functions as an activator suppressing NrtR repressor activity. The presence of high ADP-ribose levels in the cell is indicative of active NAD turnover in bacteria, which could signal the activation of NAD biosynthetic gene expression via inhibiting the repressor function of NrtR. By comparing the crystal structures of NrtR in complex with DNA and with ADP-ribose, we identified a "Nudix switch" element that likely plays a critical role in the allosteric regulation of DNA binding and repressor function of NrtR.


Subject(s)
Adenosine Diphosphate Ribose/physiology , Adenosine Diphosphate/physiology , Models, Molecular , NAD/metabolism , Sirtuins/physiology , Adenosine Diphosphate/metabolism , Adenosine Diphosphate Ribose/metabolism , Binding Sites , Crystallography, X-Ray , DNA, Fungal/isolation & purification , DNA, Fungal/metabolism , Hydrogen Bonding , Protein Conformation , RNA, Fungal/isolation & purification , RNA, Fungal/metabolism , Saccharomyces/chemistry , Saccharomyces/cytology , Saccharomyces/growth & development , Sirtuins/metabolism , Templates, Genetic , Transcription, Genetic
6.
Med Hypotheses ; 71(2): 283-5, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18417297

ABSTRACT

Poly(ADP-ribose) is found to be involved in many physiological or pathological processes. It is mainly modulated by poly(ADP-ribose) polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG). Either PARP or PARG is associated with the neuronal death in a variety of neurodegenerative diseases. Cumulative data have suggested that poly(ADP-ribose) regulation might have a therapeutic value in neurotoxicity-induced neuron damage, probably due to the inhibition of apoptosis, suppressing of inflammation and activation of cell survival signaling. We hypothesize poly(ADP-ribose) play an important role in seizures-induced neuron death. Seizures can lead to neuron degeneration as for the exitotoxity of glutamate. Recently, it is indicated seizures also can trigger PARP activation. Further investigation is needed to determine whether poly(ADP-ribose) signal is a therapeutic target for seizures-induced injury.


Subject(s)
Adenosine Diphosphate Ribose/metabolism , Neurons/pathology , Seizures/metabolism , Adenosine Diphosphate Ribose/physiology , Apoptosis , Cell Communication , Cell Death , Cell Survival , Glutamic Acid/metabolism , Humans , Inflammation , Models, Biological , Models, Theoretical , Neurodegenerative Diseases/metabolism , Neurons/metabolism , Signal Transduction
7.
Neurochem Res ; 33(7): 1256-62, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18259858

ABSTRACT

A melastatin-like transient receptor potential 2 (TRPM2) channel is activated in concert with Ca2+ by intracellular adenosine diphosphoribose (ADPR) binding to the channel's enzyme Nudix domain. Channel activity is also seen with nicotinamide dinucleotide (NAD+) and hydrogen peroxide (H2O2) although the mechanisms remain unknown. Hence, we tested the effects of ADPR, NAD+ and H2O2 on the activation of TRPM2 currents in transfected Chinese hamster ovary (CHO) cells. The CHO cells were transfected with cDNA coding for TRPM2. The intracellular solution used EDTA (10 mM) as a chelator for Ca2+ and heavy metal ions. Moreover, we balanced the intracellular Ca2+ concentration at 1 microM. H2O2 (10 mM) in the bath chamber was extracellularly added although ADPR (0.3 mM) and NAD+ (1 mM) in pipette solution were intracellularly added. Using these conditions, the channel currents were evoked by the three stimulators. The time course of ADPR, NAD+ and H2O2 effects was characterized by a delay of 0.6, 3.0 min and 2-5 min, respectively and a slow current induction reached a clear plateau with ADPR and NAD+ although H2O2 currents continued to gain in amplitude over at least 15 min and it did not reach a clear plateau in many experiments. Furthermore, H2O2-induced a single-channel conductance in the current study; the first time that this has been resolved in CHO. The conductance of ADPR and H2O2 was 48.80 pS and 39.14 pS, respectively and the cells seem to be separately activated by ADPR and H2O2. In conclusion, we observed further support for a calcium influx pathway regulated separately by oxidative stress and ADPR in TRPM2 channels in transfected cells. A second novel result of the present study was that the TRPM2 channels were constitutionally activated by H2O2.


Subject(s)
Adenosine Diphosphate Ribose/physiology , Calcium Signaling/physiology , Calcium/metabolism , Oxidative Stress/physiology , TRPM Cation Channels/physiology , Animals , CHO Cells , Cricetinae , Cricetulus , Electrophysiology , Hydrogen Peroxide/pharmacology , NAD/physiology , Oxidants/pharmacology , Patch-Clamp Techniques , Transfection
8.
Neuroscience ; 151(2): 525-32, 2008 Jan 24.
Article in English | MEDLINE | ID: mdl-18093742

ABSTRACT

Human immunodeficiency virus (HIV)-1 Tat is a multifunctional protein involved in viral replication, inflammation and apoptosis. Tat activates phospholipase C-beta (PLC-beta), presumably via a pertussis toxin (PTX) sensitive G(i) protein, which is critical for neuronal apoptosis. In this study, we show that Tat-mediated intracellular Ca(2+) release in rat pheochromocytoma (PC-12) cells and rat primary cortical neuronal cultures was abrogated by pretreatment with either pertussis toxin and/or its B-oligomer subunit (PTX-B), devoid of ADP ribosyltransferase activity. PTX-B pretreatment also inhibited intracellular Ca(2+) release by bradykinin and 2,4,6-trimethyl-N-(m-3-trifluoromethylphenyl) benzenesulfonamide (m-3M3FBS), a director activator of phospholipase C. Activation of protein kinase C (PKC) by phorbol 12,13-dibutyrate (PdBu) mimicked the PTX-B-mediated inhibition of m-3M3FBS-stimulated intracellular Ca(2+) increase, while inhibition of PKC by bisindolylmaleimide I hydrochloride (BIM) reversed the inhibitory action of PTX-B. Functionally, PTX-B reduced Tat-induced Bax and caspase-3 proteins and reduced cell apoptosis. We conclude that PTX inhibition of Tat-mediated intracellular Ca(2+) release is independent of ADP ribosylation of the G(i) protein via the A protomer, but mediated by the B-oligomer. Furthermore, PTX-B suppresses HIV-1 Tat-mediated apoptosis by reducing its activation of PLC-beta through a PKC activation pathway.


Subject(s)
Apoptosis/drug effects , Enzyme Inhibitors/pharmacology , Neurons/drug effects , Pertussis Toxin/pharmacology , Phospholipase C beta/antagonists & inhibitors , Protein Kinase C/physiology , tat Gene Products, Human Immunodeficiency Virus/antagonists & inhibitors , tat Gene Products, Human Immunodeficiency Virus/toxicity , Adenosine Diphosphate Ribose/physiology , Animals , Calcium/metabolism , Cerebral Cortex/cytology , Cerebral Cortex/drug effects , Electrophoresis, Polyacrylamide Gel , Feedback, Physiological , GTP-Binding Protein alpha Subunits, Gi-Go/physiology , Immunohistochemistry , Neurons/pathology , PC12 Cells , Rats
9.
Usp Fiziol Nauk ; 37(1): 3-17, 2006.
Article in Russian | MEDLINE | ID: mdl-16522000

ABSTRACT

Functions and possible mechanisms of action of adenosine diphosphate ribose (ADP-ribose) and its cyclic analogue--cycle-ADP-ribose (cADP-ribose)-- substances pretend to role of novel second messengers are reviewed. Possible mechanisms of ADP-ribose and cADP-ribose synthesis regulation and metabolism are analyzed. Prospective mechanisms of ADP-ribose and cADP-ribose transportation into the cell are described. ADP-ribose and cADP-ribose are considered as endogenous regulators of ionic balance (in particular regulators of calcium balance) in different tissues. Effects of ADP-ribose on isolated heart of frog and warm-blooded animal (rat), as well as on rat heart in vivo are discussed. The role of ionic channels and receptors, gated by ADP- and cADP-ribose in regulation of cardiomyocyte ionic balance in normal and pathological condition are analyzed. The possible role of purine receptors in ADP-ribose and cADP-ribose effects on heart are discussed.


Subject(s)
Adenosine Diphosphate Ribose/physiology , Calcium/metabolism , Heart/drug effects , Myocardium/metabolism , Adenosine Diphosphate Ribose/metabolism , Adenosine Diphosphate Ribose/pharmacology , Animals , Cyclic ADP-Ribose/metabolism , Cyclic ADP-Ribose/pharmacology , Cyclic ADP-Ribose/physiology , Heart/physiology , Humans , Myocardial Contraction/drug effects , Potassium Channels/metabolism , Receptors, Purinergic/metabolism
10.
J Biol Chem ; 281(5): 2489-96, 2006 Feb 03.
Article in English | MEDLINE | ID: mdl-16316998

ABSTRACT

Stimulation of Jurkat T cells by high concentrations of concanavalin A (ConA) induced an elevation of the endogenous adenosine diphosphoribose (ADPR) concentration and an inward current significantly different from the Ca2+ release-activated Ca2+ current (I(CRAC)). Electrophysiological characterization and activation of a similar current by infusion of ADPR indicated that the ConA-induced current is carried by TRPM2. Expression of TRPM2 in the plasma membrane of Jurkat T cells was demonstrated by reverse transcription-PCR, Western blot, and immunofluorescence. Inhibition of ADPR formation reduced ConA-mediated, but not store-operated, Ca2+ entry and prevented ConA-induced cell death of Jurkat cells. Moreover, gene silencing of TRPM2 abolished the ADPR- and ConA-mediated inward current. Thus, ADPR is a novel second messenger significantly involved in ConA-mediated cell death in T cells.


Subject(s)
Adenosine Diphosphate Ribose/metabolism , Adenosine Diphosphate Ribose/physiology , Calcium/metabolism , Second Messenger Systems/physiology , T-Lymphocytes/metabolism , Cell Death , Concanavalin A/pharmacology , Electrophysiology , Humans , Jurkat Cells , Lymphocyte Activation/drug effects , TRPM Cation Channels/analysis , TRPM Cation Channels/genetics , TRPM Cation Channels/metabolism
11.
Pflugers Arch ; 451(1): 212-9, 2005 Oct.
Article in English | MEDLINE | ID: mdl-15952035

ABSTRACT

A unique functional property within the transient receptor potential (TRP) family of cation channels is the gating of TRP (melastatin) 2 (TRPM2) channels by ADP-ribose (ADPR). ADPR binds to the intracellular C-terminal tail of TRPM2, a domain that shows homology to enzymes with pyrophosphatase activity. Cytosolic Ca(2+) enhances TRPM2 gating by ADPR; ADPR and Ca(2+) in concert may be an important messenger system mediating Ca(2+) influx. Other stimuli of TRPM2 include NAD and H(2)O(2) and cyclic ADPR, which may act synergistically with ADPR. H(2)O(2), an experimental paradigm of oxidative stress, may also induce the formation of ADPR in the nucleus or mitochondria. In this review, we summarize the gating properties of TRPM2 and the proposed pathways of channel activation in vivo. TRPM2 is likely to be a key player in several signalling pathways, mediating cell death in response to oxidative stress or in reperfusion injury. Moreover, it plays a decisive role in experimentally induced diabetes mellitus and in the activation of leukocytes.


Subject(s)
Adenosine Diphosphate Ribose/physiology , Calcium/metabolism , Oxidative Stress/physiology , TRPM Cation Channels/physiology , Animals , Cyclic ADP-Ribose/physiology , Drug Synergism , Humans , Hydrogen Peroxide/pharmacology , Poly(ADP-ribose) Polymerases/physiology , Second Messenger Systems/physiology , TRPM Cation Channels/chemistry , TRPM Cation Channels/drug effects , TRPM Cation Channels/genetics
14.
Biochem J ; 382(Pt 3): 849-56, 2004 Sep 15.
Article in English | MEDLINE | ID: mdl-15233622

ABSTRACT

Ca(2+) ions play a critical role in the biochemical cascade of signal transduction pathways, leading to the activation of immune cells. In the present study, we show that the exposure of freshly isolated human monocytes to NAD(+) results in a rapid concentration-dependent elevation of [Ca(2+)](i) (intracellular free Ca(2+) concentration) caused by the influx of extracellular Ca(2+). NAD(+) derivatives containing a modified adenine or nicotinamide ring failed to trigger a Ca(2+) increase. Treating monocytes with ADPR (ADP-ribose), a major degradation product of NAD(+), also resulted in a rise in [Ca(2+)](i). Selective inhibition of CD38, an NAD-glycohydrolase that generates free ADPR from NAD(+), does not abolish the effect of NAD(+), excluding the possibility that NAD(+) might act via ADPR. The NAD(+)-induced Ca(2+) response was prevented by the prior addition of ADPR and vice versa, indicating that both compounds share some mechanisms mediating the rise in [Ca(2+)](i). NAD(+), as well as ADPR, were ineffective when applied following ATP, suggesting that ATP controls events that intersect with NAD(+) and ADPR signalling.


Subject(s)
Adenosine Diphosphate Ribose/physiology , Calcium/metabolism , Monocytes/metabolism , NAD/physiology , ADP-ribosyl Cyclase/antagonists & inhibitors , ADP-ribosyl Cyclase 1 , Adenosine Triphosphate/physiology , Antigens, CD , Cells, Cultured , Cytosol/metabolism , Humans , Membrane Glycoproteins , NAD/analogs & derivatives , Signal Transduction/physiology
15.
J Immunol ; 170(3): 1167-73, 2003 Feb 01.
Article in English | MEDLINE | ID: mdl-12538672

ABSTRACT

Phagocytosis is associated with large changes in the membrane potential of macrophages, but the functional significance of this is unknown. Whole cell recordings were made from rat peritoneal macrophages. Sustained (>30 s) depolarization of the cells progressively activated a conductance that remained high (several nanoSeimens) for several tens of seconds. This current: 1) was linearly dependent on potential between -100 and +50 mV; 2) reversed close to 0 mV in a physiological external solution; 3) could also be carried in part by N-methyl-D-glucamine (P(NMDG)/P(Na) 0.7), chloride (P(Cl)/P(Na) 0.5), or calcium (P(Ca)/P(Na) 1.3); and 4) was blocked by intracellular ATP (5 mM) or ADP (10 mM) and by extracellular lanthanum (half-maximal concentration 1 mM). A current with all the same properties was recorded in cells when the intracellular solution contained ADP-ribose (10-300 micro M) or beta-NAD (1 mM) (but not any other nucleotide analogs tested). The results suggest that prolonged depolarization leads to an increased intracellular level of ADP-ribose, which in turn activates this nonselective conductance(s).


Subject(s)
Adenosine Diphosphate Ribose/physiology , Ion Channels/metabolism , Macrophages, Peritoneal/metabolism , Sorbitol/analogs & derivatives , Animals , Calcium Channels/metabolism , Cell Line , Cell Membrane Permeability/drug effects , Cell Membrane Permeability/physiology , Cells, Cultured , Chloride Channels/metabolism , Lanthanum/pharmacology , Macrophages, Peritoneal/drug effects , Male , Membrane Potentials/drug effects , Membrane Potentials/physiology , Patch-Clamp Techniques , Rats , Rats, Wistar , Sodium Channels/metabolism , Sorbitol/metabolism , Spin Labels , Thiocarbamates/metabolism
16.
J Biol Chem ; 277(26): 23150-6, 2002 Jun 28.
Article in English | MEDLINE | ID: mdl-11960981

ABSTRACT

LTRPC2 is a cation channel recently reported to be activated by adenosine diphosphate-ribose (ADP-ribose) and NAD. Since ADP-ribose can be formed from NAD and NAD is elevated during oxidative stress, we studied whole cell currents and increases in the intercellular free calcium concentration ([Ca(2+)](i)) in long transient receptor potential channel 2 (LTRPC2)-transfected HEK 293 cells after stimulation with hydrogen peroxide (H(2)O(2)). Cation currents carried by monovalent cations and Ca(2+) were induced by H(2)O(2) (5 mm in the bath solution) as well as by intracellular ADP-ribose (0.3 mm in the pipette solution) but not by NAD (1 mm). H(2)O(2)-induced currents developed slowly after a characteristic delay of 3-6 min and receded after wash-out of H(2)O(2). [Ca(2+)](i) was rapidly increased by H(2)O(2) in LTRPC2-transfected cells as well as in control cells; however, in LTRPC2-transfected cells, H(2)O(2) evoked a second delayed rise in [Ca(2+)](i). A splice variant of LTRPC2 with a deletion in the C terminus (amino acids 1292-1325) was identified in neutrophil granulocytes. This variant was stimulated by H(2)O(2) as the wild type. However, it did not respond to ADP-ribose. We conclude that activation of LTRPC2 by H(2)O(2) is independent of ADP-ribose and that LTRPC2 may mediate the influx of Na(+) and Ca(2+) during oxidative stress, such as the respiratory burst in granulocytes.


Subject(s)
Adenosine Diphosphate Ribose/physiology , Calcium Channels/drug effects , Hydrogen Peroxide/pharmacology , Ion Channels , Membrane Proteins , Adult , Base Sequence , Calcium/metabolism , Calcium Channels/genetics , Calcium Channels/metabolism , Cloning, Molecular , Humans , Molecular Sequence Data , NAD/pharmacology , Oxidative Stress , TRPM Cation Channels
17.
FASEB J ; 16(7): 697-705, 2002 May.
Article in English | MEDLINE | ID: mdl-11978734

ABSTRACT

cADPR, a potent calcium-mobilizing intracellular messenger synthesized by ADP-ribosyl cyclases regulates openings of ryanodine receptors (RyR). Here we report that in the rat testis, a functional cADPR Ca2+ release system is essential for the contractile response of peritubular smooth muscle cells (PSMC) to endothelin (ET). We previously showed that this potent smooth muscle agonist elicits intracellular Ca2+ release in PSMC and seminiferous tubule contraction via activation of ETA and ETB receptors. ETB-R induces the mobilization of a thapsigargin-sensitive but IP3-independent intracellular Ca2+ pool. Stimulation of permeabilized PSMC with cADPR was found to elicit large Ca2+ releases blocked by either a selective antagonist of cADPR or a RyR blocker, but not by heparin. Western blotting and confocal fluorescence microscopy indicated the specific expression of type 2 RyR in perinuclear localization. ET was found to stimulate the activity of ADP-ribosyl cyclase. Microinjection of the selective cADPR antagonist 8NH2-cADPR completely abolished subsequent stimulation of Ca2+ signaling via ETA and ETB receptors. cADPR therefore appears to have an obligatory role for ETA-R and ETB-R-mediated calcium signaling in PSMC. However, ETB-R seem to be coupled exclusively to cADPR whereas ETA-R activation may be linked to IP3 and cADPR signaling pathways.


Subject(s)
Adenosine Diphosphate Ribose/analogs & derivatives , Adenosine Diphosphate Ribose/pharmacology , Antigens, CD , Calcium Signaling , Endothelin-1/pharmacology , Muscle Contraction , Muscle, Smooth/physiology , Seminiferous Tubules/physiology , ADP-ribosyl Cyclase , ADP-ribosyl Cyclase 1 , Adenosine Diphosphate Ribose/antagonists & inhibitors , Adenosine Diphosphate Ribose/physiology , Animals , Antigens, Differentiation/metabolism , Blotting, Western , Boron Compounds/chemistry , Calcium Channels/metabolism , Calcium Signaling/drug effects , Cell Membrane/enzymology , Cells, Cultured , Culture Techniques , Cyclic ADP-Ribose , Endothelins/pharmacology , Fluorescent Dyes/chemistry , Inositol 1,4,5-Trisphosphate Receptors , Male , Membrane Glycoproteins , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/ultrastructure , NAD+ Nucleosidase/metabolism , Peptide Fragments/pharmacology , Rats , Receptor, Endothelin B , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Endothelin/agonists , Ryanodine/metabolism , Ryanodine/pharmacology , Ryanodine Receptor Calcium Release Channel/analysis , Seminiferous Tubules/cytology , Seminiferous Tubules/ultrastructure
18.
EMBO J ; 21(5): 909-19, 2002 Mar 01.
Article in English | MEDLINE | ID: mdl-11867519

ABSTRACT

In pancreatic acinar cells, low, threshold concentrations of acetylcholine (ACh) or cholecystokinin (CCK) induce repetitive local cytosolic Ca2+ spikes in the apical pole, while higher concentrations elicit global signals. We have investigated the process that transforms local Ca2+ spikes to global Ca2+ transients, focusing on the interactions of multiple intracellular messengers. ACh-elicited local Ca2+ spikes were transformed into a global sustained Ca2+ response by cyclic ADP-ribose (cADPR) or nicotinic acid adenine dinucleotide phosphate (NAADP), whereas inositol 1,4,5-trisphosphate (IP3) had a much weaker effect. In contrast, the response elicited by a low CCK concentration was strongly potentiated by IP3, whereas cADPR and NAADP had little effect. Experiments with messenger mixtures revealed a local interaction between IP3 and NAADP and a stronger global potentiating interaction between cADPR and NAADP. NAADP strongly amplified the local Ca2+ release evoked by a cADPR/IP3 mixture eliciting a vigorous global Ca2+ response. Different combinations of Ca2+ releasing messengers can shape the spatio-temporal patterns of cytosolic Ca2+ signals. NAADP and cADPR are emerging as key messengers in the globalization of Ca2+ signals.


Subject(s)
Adenosine Diphosphate Ribose/analogs & derivatives , Adenosine Diphosphate Ribose/physiology , Calcium Signaling/physiology , Inositol 1,4,5-Trisphosphate/physiology , NADP/analogs & derivatives , NADP/physiology , Second Messenger Systems/physiology , Acetylcholine/pharmacology , Animals , Caffeine/pharmacology , Calcium Channels/drug effects , Calcium Channels/physiology , Calcium Signaling/drug effects , Cell Polarity , Cholecystokinin/pharmacology , Cyclic ADP-Ribose , Exocytosis/drug effects , Inositol 1,4,5-Trisphosphate/pharmacology , Inositol 1,4,5-Trisphosphate Receptors , Mice , NADP/pharmacology , Pancreas/cytology , Patch-Clamp Techniques , Receptors, Cell Surface/drug effects , Receptors, Cell Surface/physiology , Receptors, Cholecystokinin/drug effects , Receptors, Cholecystokinin/physiology , Receptors, Cholinergic/drug effects , Receptors, Cholinergic/physiology , Receptors, Cytoplasmic and Nuclear/drug effects , Receptors, Cytoplasmic and Nuclear/physiology , Sincalide/pharmacology
19.
Cell Signal ; 13(12): 895-9, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11728829

ABSTRACT

Contact of Jurkat T-lymphocytes with the extracellular matrix (ECM) protein laminin resulted in long-lasting alpha6beta1-integrin-mediated Ca(2+) signalling. Both Ca(2+) release from thapsigargin-sensitive Ca(2+) stores and capacitative Ca(2+) entry via Ca(2+) channels sensitive to SKF 96365 constitute important parts of this process. Inhibition of alpha6beta1-integrin-mediated Ca(2+) signalling by (1) the src kinase inhibitor PP2, (2) the PLC inhibitor U73122, and (3) the cyclic adenosine diphosphoribose (cADPR) antagonist 7-deaza-8-Br-cADPR indicate the involvement of src tyrosine kinases and the Ca(2+)-releasing second messengers D-myo-inositol 1,4,5-trisphosphate (InsP3) and cADPR.


Subject(s)
Adenosine Diphosphate Ribose/analogs & derivatives , Calcium Signaling , Integrins/physiology , T-Lymphocytes/immunology , Adenosine Diphosphate Ribose/antagonists & inhibitors , Adenosine Diphosphate Ribose/pharmacology , Adenosine Diphosphate Ribose/physiology , Calcium Channel Blockers/pharmacology , Calcium Signaling/drug effects , Cyclic ADP-Ribose , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Estrenes/pharmacology , Humans , Imidazoles/pharmacology , Integrin alpha6beta1 , Jurkat Cells , Kinetics , Laminin/pharmacology , Pyrimidines/pharmacology , Pyrrolidinones/pharmacology , T-Lymphocytes/drug effects , Thapsigargin/pharmacology , Type C Phospholipases/antagonists & inhibitors , Type C Phospholipases/physiology , src-Family Kinases/antagonists & inhibitors , src-Family Kinases/physiology
20.
Proc Natl Acad Sci U S A ; 98(26): 14859-64, 2001 Dec 18.
Article in English | MEDLINE | ID: mdl-11752433

ABSTRACT

Sponges (phylum Porifera) are the phylogenetically oldest metazoan animals, their evolution dating back to 600 million years ago. Here we demonstrate that sponges express ADP-ribosyl cyclase activity, which converts NAD(+) into cyclic ADP-ribose, a potent and universal intracellular Ca(2+) mobilizer. In Axinella polypoides (Demospongiae, Axinellidae), ADP-ribosyl cyclase was activated by temperature increases by means of an abscisic acid-induced, protein kinase A-dependent mechanism. The thermosensor triggering this signaling cascade was a heat-activated cation channel. Elucidation of the complete thermosensing pathway in sponges highlights a number of features conserved in higher organisms: (i) the cation channel thermoreceptor, sensitive to heat, mechanical stress, phosphorylation, and anesthetics, shares all of the functional characteristics of the mammalian heat-activated background K(+) channel responsible for central and peripheral thermosensing; (ii) involvement of the phytohormone abscisic acid and cyclic ADP-ribose as its second messenger is reminiscent of the drought stress signaling pathway in plants. These results suggest an ancient evolutionary origin of this stress-signaling cascade in a common precursor of modern Metazoa and Metaphyta.


Subject(s)
Abscisic Acid/physiology , Adenosine Diphosphate Ribose/physiology , Antigens, CD , Ion Channel Gating , Ion Channels/physiology , Porifera/metabolism , Signal Transduction , ADP-ribosyl Cyclase , ADP-ribosyl Cyclase 1 , Abscisic Acid/biosynthesis , Animals , Antigens, Differentiation/metabolism , Chromatography, High Pressure Liquid , Cyclic AMP-Dependent Protein Kinases/metabolism , Enzyme Activation , Hot Temperature , Ion Channels/metabolism , NAD+ Nucleosidase/metabolism , Porifera/enzymology , Spectrometry, Fluorescence
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