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PubMed1994

Cyclic ADP-ribose, the ADP-ribosyl cyclase pathway and calcium signalling.

Cyclic adenosine diphosphate-ribose, an endogenous metabolite of nicotinamide adenine dinucleotide was first characterized as a potent Ca2+ mobilizing agent in sea urchin eggs. Mounting evidence points to it being an endogenous activator of Ca(2+)-induced Ca2+ release by non-skeletal muscle ryanodine receptors in several invertebrate and mammalian cell types. Cyclic adenosine diphosphate-ribose is synthesized by adenosine diphosphate-ribosyl cyclases, which have been found to be widespread enzymes. Recent data suggests that cyclic adenosine diphosphate-ribose may function as a second messenger in sea urchin eggs at fertilization and in stimulus secretion coupling in pancreatic beta-cells. A second messenger role for cyclic adenosine diphosphate-ribose requires that its intracellular levels be under the control of extracellular stimuli. Another second messenger, cGMP, stimulates the synthesis of cyclic adenosine diphosphate-ribose from nicotinamide adenine dinucleotide by activating the adenosine diphosphate-ribosyl cyclase pathway in sera urchin eggs and egg homogenates, suggesting that cyclic adenosine diphosphate-ribose may be an intracellular messenger for cell surface receptors or nitric oxide, which activate cGMP-producing guanylate cyclases. Cyclic adenosine diphosphate-ribose may have a similar role to inositol trisphosphate in controlling intracellular calcium signalling with these two calcium-mobilizing second messengers activating ryanodine receptors and inositol trisphosphate receptors respectively.

ADP-ribosyl Cyclase↗

PubMed2004

Expression of protease-activated receptors (PARs) in OLN-93 oligodendroglial cells and mechanism of PAR-1-induced calcium signaling.

Protease-activated receptors (PARs) are a group of four members of the superfamily of G protein-coupled receptors that transduce cell signaling by proteolytic activity of extracellular serine proteases, such as thrombin. Possible expression and functions of PARs in oligodendrocytes, the myelin forming cells of the CNS, are still unclear. Here, the oligodendrocyte cell line OLN-93 was used to investigate the signaling of PARs. By reverse transcription-polymerase chain reaction (RT-PCR), immunostaining and Ca(2+) imaging studies, we demonstrate that OLN-93 cells functionally express PAR-1. PAR-3 seems to be expressed without apparent activity, and PAR-2 and PAR-4 cannot be detected. Short-term stimulation of the OLN-93 cells with PAR-1 agonists, such as thrombin, trypsin and PAR-1 activating peptide, dose-dependently induced a transient rise of [Ca(2+)](i). Concentration-effect curves display a sigmoidal concentration dependence. Elevation of [Ca(2+)](i) induced by PAR-1 mainly resulted from Ca(2+) release from intracellular stores. Studies on the effects of pertussis toxin (PTX), phospholipase C antagonist and 2-APB, showed that in OLN-93 cells (i). the calcium signaling cascade from PAR-1 was mediated through PTX-insensitive G proteins, (ii). activation of phospholipase C and liberation of InsP(3) were events upstream of the Ca(2+) release from the stores. In addition, the present study analyzed PAR-1 desensitization caused by exposure to thrombin, trypsin, and PAR-1 activating peptide, elucidated the influence of the protease cathepsin G on PAR-1 activation, and also characterized PAR-1 desensitization. This is the first study, which shows that OLN-93 oligodendrocytes functionally express PAR-1, and identifies the receptor coupling to mobilization of intracellular calcium. Moreover, the expression of PAR-1 was demonstrated by RT-PCR in primary oligodendrocytes from rat brain.

Animals↗

PubMed1998

Modulation of calcium signalling by intracellular pH in exocrine acinar cells.

Cell-permeant weak acids and bases alter the rate of fluid and electrolyte secretion by a range of epithelia, including the exocrine glands. It is widely assumed that weak acids and bases exert these effects by participating in the ion transport mechanism, or by changing intracellular pH (pHi) and hence modulating electrolyte (ion) transporters. An alternative possibility is that these substances act by modifying the intracellular calcium signals which control fluid secretion. In the present study we have examined whether weak acids and bases modify intracellular free calcium ([Ca2+]i) in exocrine acinar cells. Alkalinization with weak bases and acidification with weak acids had quite different effects on [Ca2+]i in resting and agonist-stimulated cells. In unstimulated lacrimal, salivary or pancreatic acinar cells, acidifying the cytosol had no effect on [Ca2+]i, while cytosolic alkalinization caused a modest rise in [Ca2+]i. This alkalinization-induced increase in [Ca2+]i appears to result from Ca2+ release from agonist-sensitive stores, and was probably caused by a small increase in intracellular InsP3 levels. In contrast, [Ca2+]i decreased when intracellular alkalinization was induced during agonist stimulation. Conversely, acidifying the cytosol during agonist stimulation raised [Ca2+]i. This latter effect was particularly dramatic in pancreatic acinar cells, where cytosolic acidification also enhanced agonist-evoked [Ca2+]i oscillations. The effects of pHi on [Ca2+]i in stimulated cells could also be observed in Ca2+-free medium, indicating that pHi altered [Ca2+]i handling by the intracellular stores rather than plasmalemmal Ca2+ transport. The results suggest that modulation of agonist-evoked [Ca2+]i signalling by changes in pHi may constitute a novel mechanism by which weak acids and bases may modulate exocrine fluid and ion transport.

Acetic Acid↗

PubMed2001

Bruton's tyrosine kinase is essential for hydrogen peroxide-induced calcium signaling.

Using Btk-deficient DT40 cells and the transfectants expressing wild-type Btk or Btk mutants in either kinase (Arg(525) to Gln), Src homology 2 (SH2, Arg(307) to Ala), or pleckstrin homology (PH, Arg(28) to Cys) domains, we investigated the roles and structure-function relationships of Btk in hydrogen peroxide-induced calcium mobilization. Our genetic evidence showed that Btk deficiency resulted in a significant reduction in hydrogen peroxide-induced calcium response. This impaired calcium signaling is correlated with the complete elimination of IP3 production and the significantly reduced tyrosine phosphorylation of PLCgamma2 in Btk-deficient DT40 cells. All of these defects were fully restored by the expression of wild-type Btk in Btk-deficient DT40 cells. The data from the point mutation study revealed that a defect at any one of the three functional domains would prevent a full recovery of Btk-mediated hydrogen peroxide-induced intracellular calcium mobilization. However, mutation at either the SH2 or PH domain did not affect the hydrogen peroxide-induced activation of Btk. Mutation at the SH2 domain abrogates both IP3 generation and calcium release, while the mutant with the nonfunctional PH domain can partially activate PLCgamma2 and catalyze IP3 production but fails to produce significant calcium mobilization. Thus, these observations suggest that Btk-dependent tyrosine phosphorylation of PLCgamma2 is required but not sufficient for hydrogen peroxide-induced calcium mobilization. Furthermore, hydrogen peroxide stimulates a Syk-, but not Btk-, dependent tyrosine phosphorylation of B cell linker protein BLNK. The overall results, together with those reported earlier [Qin et al. (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 7118], are consistent with the notion that functional SH2 and PH domains are required for Btk to form a complex with PLCgamma2 through BLNK in order to position the Btk, PLCgamma2, and phosphatidylinositol 4,5-bisphosphate in close proximity for efficient activation of PLCgamma2 and to maximize its catalytic efficiency for IP3 production.

Adaptor Proteins, Signal Transducing↗

PubMed1997

Cyclosporin A-sensitive calcium signaling represses NFkappaB activation in human bronchial epithelial cells and enhances NFkappaB activation in Jurkat T-cells.

Activation of the NFkappaB transcription factor in 16HBE human bronchial epithelial cells was compared with activation of NFkappaB in Jurkat T-cells. An NFkappaB-luciferase reporter gene was activated by phorbol myristyl acetate (PMA) in both cell types. Ionomycin added to PMA (P/I) inhibited NFkappaB activation in epithelial cells and enhanced PMA activation in T-cells. Cyclosporin A (CsA) inhibited calcium signaling in both cell types. Nuclear NFkappaB DNA-binding stimulated with PMA was inhibited with ionomycin in epithelial cells and was enhanced with ionomycin in T-cells; CsA reversed both effects of ionomycin. Cytosolic IkappaB-alpha was regulated identically in both cell types. Thus, calcium activated opposing nuclear signaling pathways in epithelial cells and T-cells. Calcium-mediated repression of NFkappaB in epithelial cells was derepressed by CsA, and this establishes a mechanism through which CsA may exert proinflammatory effects in nonlymphoid cells.

Base Sequence↗

PubMed1999

Staurosporine enhances parathyroid hormone-induced calcium signal in UMR-106 osteoblastic cells.

Parathyroid hormone (PTH) treatment of bone and kidney-derived cells not only activates adenylyl cyclase but also increases intracellular free calcium, and translocates protein kinase C (PKC) from cytosol to plasma membranes. We have found that acute phorbol ester pretreatment significantly decreases PTH-induced calcium transients and the effect of phorbol ester was antagonized by staurosporine (ST). Although the major effect of ST in that study was the reversal of the action of phorbol ester, it appeared that ST may also have promoted the effect of PTH directly. To further investigate the observation, we examined the effect of ST on the intracellular calcium transients induced by PTH and alpha-thrombin (alpha-TH). For calcium transient experiments, UMR-106 cells were loaded with 2 mM fluo-acetoxymethylester for 30 min at room temperature. The cells were then washed and suspended in buffer containing 1 mM calcium. Fluorescence was detected at 530 nm, with excitation at 505 nm. ST alone did not cause calcium transients, but enhanced the transients elicited by PTH when added 5 min before the hormone. Another protein kinase inhibitor H-7 likewise enhanced the calcium responses elicited by PTH, while genistein did not affect PTH response. Calcium transients elicited by alpha-TH were also enhanced by ST. The results suggest that there might be tonically activated endogenous protein kinase(s) which inhibit calcium signaling of some calcemic agents.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMedDate not supplied

Single cell observation of calcium signals in class II specific killer T cells.

A confocal fluorescence microscope with an argon ion laser and a digital imaging fluorescence microscope were used to study calcium signals in class II-specific killer T cells after interaction with target cells. Here, we used two kinds of I-Ak specific allogeneic killer T cell clones, QM11 (CD8+) and QM56 (CD4+), and target cells, B10.A spleen cells (I-Ak) and B cell hybridomas (TP67.21, I-Ak). After interaction with target cells, the intracellular free calcium ion concentration ([Ca2+]i) in QM11 cells (CD8+) increased rapidly with short lag-times (several seconds). The [Ca2+]i in QM56 cells (CD4+), however, increased with much longer lag-times (hundreds of seconds). The results were consistent with previous findings that the cytolytic activity of QM11 cells (CD8+) was much greater than that of QM56 cells (CD4+).

Animals↗

PubMed2000

Calcium signalling during RVD of kidney cells.

The balance of a high extracellular osmolarity in the kidney medulla is mainly based on an accumulation of organic osmolytes in the cells. The regulation of cell volume during hypotonic conditions results in a release of organic osmolytes - a process that is partly calcium-dependent. Using calcium-sensitive fluorescent dye and confocal laser scanning microscopy, we have investigated calcium signalling during regulatory volume decrease (RVD) in kidney cells. In rat inner medullary collecting duct (IMCD) cells in primary culture, hypotonic stress induced a calcium release from intracellular stores that preceded calcium entry from the extracellular milieu. Hyposmotic stress had no effect on the cellular IP(3) content. Preincubation with 100 micromol/l ETYA (a non-metabolizible derivative of arachidonic acid), however, reduced the calcium response to hypotonic stress as well as the RVD. Blocker of voltage-dependent calcium channels (verapamil, diltiazem, and nifedipine) in the concentration of 40 micromol/l reduced partly the calcium response. SKF-96365, an inhibitor of receptor-mediatedcalcium channels, also attenuated the calcium influx. In conclusion, swelling of IMCD cells increases intracellular calcium by release from intracellular stores and entry across the cell membranes. The signalling involves arachidonic acid metabolism.

Calcium↗

PubMed1993

Evidence for stereospecific inositol 1,3,4,5-[3H]tetrakisphosphate binding sites on rat liver nuclei. Delineating inositol 1,3,4,5-tetrakisphosphate interaction in nuclear calcium signaling process.

3H-Labeled inositol 1,3,4,5-tetrakisphosphate (IP4) binding sites are observed on nuclei isolated from rat liver and devoid of any microsomal, mitochondrial, or plasma membrane constituents. A pH of about 6.5 is found optimum for maximum [3H]IP4 specific binding that is sensitive to changes in pH. The [3H]IP4 binding on the nuclei can be distinguished into a high affinity site and a low affinity site. The two binding sites are characterized by distinct KD and Bmax (1.6 nM versus 57.0 nM KD; 0.25 pmol/mg protein and 3.7 pmol/mg protein Bmax). IP4 is capable of 45Ca2+ uptake even in the absence of ATP. The calcium uptake by nuclei is highly sensitive to IP4 since it is achieved even at 1 nM IP4 concentration. Furthermore, data are documented demonstrating that a rapid and transient 45Ca2+ release by inositol 1,4,5-trisphosphate (IP3) from the intact nuclei can be reversed by IP4. The presence of IP3 potentiates the action of IP4 in nuclear calcium reuptake as attested by the rate of calcium uptake by IP4 in the absence of IP3 (0.16 nmol/s/mg of protein) and in the presence of IP3 (4.0 nmol/s/mg of protein). A novel mechanism of nuclear calcium signaling is proposed where IP4 brings calcium into the nuclei mediated by its specific putative binding sites.

Animals↗

PubMed2002

Gamma-aminobutyric acid-induced calcium signalling in rat superior collicular neurones.

Ionotropic gamma-aminobutyric acid (GABA) receptors are known to mediate excitation in neonatal neurones as a crucial developmental factor. In the present study we employed calcium imaging techniques with the calcium indicator Fura-2-AM to study the pharmacology of GABA-induced calcium responses in cultures prepared from neonatal rat superficial superior colliculus (SC), after immunocytochemical labelling confirmed the presence of GABA(C) rho(1) subunits in 35% of neurones. Rises in neuronal intracellular calcium were obtained in response to GABA and also to the subtype-specific GABA(A) agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol. However, the GABA(C) agonist cis-4-aminocrotonic acid induced calcium response only at unspecifically high concentrations (500 microM). Co-application of GABA antagonists revealed that both GABA(A&C) agonists' actions could be blocked by the GABA(A) antagonist bicuculline but not the GABA(C) antagonists 1,2,5,6-tetrahydro-(pyridin-4-yl) methylphosphinic acid. This suggests that activation of GABA(A) but not GABA(C) receptors contributes to excitatory GABA responses and related calcium signals in neonatal SC neurones.

Animals↗

PubMed2004

Calcium signaling is involved in dynein-dependent microtubule organization.

The microtubule cytoskeleton supports cellular morphogenesis and polar growth, but the underlying mechanisms are not understood. In a screen for morphology mutants defective in microtubule organization in the fungus Ustilago maydis, we identified eca1 that encodes a sarcoplasmic/endoplasmic calcium ATPase. Eca1 resides in the endoplasmic reticulum and restores growth of a yeast mutant defective in calcium homeostasis. Deletion of eca1 resulted in elevated cytosolic calcium levels and a severe growth and morphology defect. While F-actin and myosin V distribution is unaffected, Deltaeca1 mutants contain longer and disorganized microtubules that show increased rescue and reduced catastrophe frequencies. Morphology can be restored by inhibition of Ca(2+)/calmodulin-dependent kinases or destabilizing microtubules, indicating that calcium-dependent alterations in dynamic instability are a major cause of the growth defect. Interestingly, dynein mutants show virtually identical changes in microtubule dynamics and dynein-dependent ER motility was drastically decreased in Deltaeca1. This indicates a connection between calcium signaling, dynein, and microtubule organization in morphogenesis of U. maydis.

Actins↗

PubMed1999

Further studies of the effects of diamide and hydrogen peroxide on calcium signaling in the human platelet.

Intracellular calcium levels were measured in Fura-2/AM loaded human platelets. Diamide (30 microM) reduced the Ca2+ response to serotonin (1 microM), but not to 4-bromo-A23187 (1 microM). The small reduction in the maximum fluorescence produced by diamide was not mirrored by a change in the sensitivity of Fura-2 pentapotassium salt to Ca2+. Changes in the spectral properties of Fura-2 thus cannot wholly explain the reduced serotonin response following diamide treatment. Hydrogen peroxide (500 microM) produced a steady increase in the observed fluorescence ratio that was partially inhibited by the phospholipase C inhibitor U-73122 (1.5 microM). In the absence of platelets, H2O2 reduced the Ca(2+)-sensitivity of Fura-2 pentapotassium salt, although it is not clear the extent to which this effect contributes to the reduction in the Ca2+ response to serotonin seen after H2O2. It is concluded that some caution may be warranted in the interpretation of the effects of H2O2 upon receptor-mediated Ca2+ signaling as measured using Fura-2.

Blood Platelets↗

PubMed2002

Calsenilin enhances apoptosis by altering endoplasmic reticulum calcium signaling.

Calsenilin (also called DREAM and KChIP3), a member of the neuronal calcium sensor family, was isolated in a yeast two-hybrid screen using an apoptotic domain of presenilin 2 as bait. Calsenilin is a cytoplasmic protein, but interacts with the COOH-termini of both presenilin 1 and presenilin 2 at the endoplasmic reticulum and the Golgi apparatus. In this study, we have investigated calsenilin's effect on apoptosis. In stable neuroglioma cell lines, we observed that calsenilin enhances apoptosis in response to serum withdrawal or thapsigargin. Consistent with these observations, caspase and apparently calpain activities were increased during apoptosis in calsenilin-overexpressing cells. Moreover, using calcium imaging we were able to show that cells treated with thapsigargin released more calcium from intracellular stores when calsenilin was overexpressed. Taken together, these data suggest that calsenilin causes cells to be more susceptible to apoptotic triggers, possibly by altering calcium dynamics.

Apoptosis↗

PubMed1990

The effects of lyotropic anions on charge movement, calcium currents and calcium signals in frog skeletal muscle fibres.

1. Intramembrane charge movement and Ca2+ currents were monitored in voltage-clamped segments of frog skeletal muscle fibres using the triple-Vaseline-gap technique. Calcium signals were measured in current-clamped fibres using either of the indicators Arsenazo III or Antipyrylazo III. 2. Non-linear capacitative currents (charge 1) were obtained using a subtraction procedure which employed either a -20 mV control pulse from a holding potential of -100 mV or alternatively a control pulse to +80 mV in depolarized fibres. The amount of charge mobilized depended on voltage according to a two-state Boltzmann function. The total charge (Qmax) was increased by ca 100% and the steepness parameter (k) by ca 70% when a +80 mV control pulse was used. 3. Thiocyanate (SCN-) and other lyotropic anions reversibly shifted the voltage dependence of mobilized charge towards negative potentials. Qmax was not significantly affected. 'Off' charge tails were greatly prolonged by lyotropic anions. 4. Extracellularly applied lyotropic anions affected the dihydropyridine-sensitive Ca2+ current by shifting the I-V relation toward more negative voltages and delaying deactivation of the tail currents. 5. The effects of lyotropic anions did not depend on whether the anion was introduced intracellularly or extracellularly. 6. Extracellular SCN- reversibly increased the peak amplitude and rate of rise of Ca signals, and decreased the latent period between stimulation and onset of the Ca signal. 7. It is concluded that lyotropic anions have similar effects on Ca2+ currents and on charge movement.

Animals↗

PubMed2002

Defective calcium signalling in uraemic platelets and its amelioration with long-term erythropoietin therapy.

BACKGROUND: Chronic renal failure (CRF) is associated with prolonged bleeding time and impaired platelet adhesion and aggregation. Erythropoietin (Epo) administration improves platelet adhesion/aggregation and ameliorates prolongation of bleeding time in CRF. However, the mechanisms of improved platelet function after Epo therapy have not been fully elucidated. The present study examined the hypothesis that the improved uraemic platelet function after Epo therapy is, in part, due to correction of the platelet calcium signalling. METHODS: Rats were randomized into four groups after 5/6 nephrectomies to produce CRF. The Epo-treated CRF group received Epo, 150 U/kg, twice weekly for 6 weeks to prevent anaemia; the felodipine and Epo-treated CRF group received Epo but was kept normotensive by felodipine treatment; the placebo-treated CRF group received placebo injections and became anaemic; and the iron-deficient CRF group received Epo but was kept anaemic by dietary iron-deficiency. A group of sham-operated rats was included as normal control. Basal and thrombin-stimulated platelet cytosolic calcium ([Ca(2+)](i)) were determined using a Ca(2+)-sensitive dye (fura-2). RESULTS: Platelets from placebo-treated CRF group exhibited a profound attenuation of thrombin-stimulated surge in [Ca(2+)](i), which is the final pathway of platelet activation. Long-term Epo administration led to a normalization of the thrombin-induced rise in platelet [Ca(2+)](i) in the CRF animals, independent of either haematocrit or blood pressure values. Further studies revealed that improved Ca(2+) signalling with Epo is associated with increased Ca(2+) uptake and expanded Ca(2+) stores in the platelets. CONCLUSIONS: The defective Ca(2+) signalling in uraemic animals and its improvement with chronic Epo therapy provides the biochemical basis of the previously reported platelet dysfunction and prolonged bleeding time in uraemic patients and animals, and their amelioration with chronic Epo therapy.

Animals↗

PubMed2004

Calcium signaling through phospholipase C activates dendritic cells to mature and is necessary for the activation and maturation of dendritic cells induced by diverse agonists.

Calcium is an important second messenger in the phospholipase C (PLC) signal transduction pathway. Calcium signaling is involved in many biological processes, including muscle contraction, cellular activation, and cellular proliferation. Dendritic cell (DC) maturation is induced by many different stimuli, including bacterial lipopolysaccharide (LPS), bacterial toxins, inflammatory cytokines, prostaglandins, as well as calcium mobilization. In the present study, we determined the role of the PLC signal transduction pathway in the activation and maturation of human monocyte-derived DCs (MDDCs) induced by diverse agonists. We found that signaling through PLC activates MDDCs to mature and is necessary for LPS, cholera toxin, dibutyryl-cyclic AMP, prostaglandin E2, and the calcium ionophore A23187 to induce MDDC maturation. The results of the present study along with the results of other studies indicate that multiple signaling pathways are involved in the activation of DCs and that inhibition of any of these pathways inhibits the maturation of DCs.

Bucladesine↗

PubMed2002

Purinergic and muscarinic modulation of the cell cycle and calcium signaling in the chick retinal ventricular zone.

Spontaneous calcium transients occur in the ventricular zone of the chick retina and result from the endogenous release of neurotransmitters in the absence of action potentials. Calcium transients resulting from the activation of purinergic and muscarinic receptors occur in a mixed population of interphase and mitotic cells, whereas those produced by ionotropic GABA and glutamate receptors are mostly restricted to the interphase population, the GABA responses primarily coming from cells that express the neuronal marker TuJ-1. Muscarinic and purinergic receptors can act respectively as a brake and an accelerator on mitosis, whereas GABA and glutamate receptors are without effect. Our results suggest that the balance between muscarinic and purinergic activation acts to control the rate of retinal proliferation in early development.

Aniline Compounds↗

PubMed1996

Calcium signals in helper T cells after interaction with antigen-specific and antigen-nonspecific B cells.

By confocal fluorescence microscopy we have studied the rises of the intracellular free calcium ion concentration ([Ca2+]i) in helper T cells (KLH-specific, I-Ak-restricted Th1 cells, 28-4) after interaction with antigen-specific and antigen-nonspecific B cells (antigen-presenting cells). Antigen-specific and antigen-nonspecific B cells were prepared by the preincubation of TNP (trinitrophenol)-specific B cell hybridomas (TP67.21 I-Ak) with TNP-conjugated KLH and KLH alone, respectively. Calcium signals in Th1 cells (28-4) were induced by antigen-specific B cells one hundred times more efficiently as those by antigen-nonspecific B cells. Herbimycin A, a tyrosine kinase inhibitor, suppressed the former signals but not the latter. These results indicated that tyrosine phosphorylation was involved in the antigen processing of antigen-specific B cells but not in the processing of antigen-nonspecific B cells.

Animals↗