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Results for “Calcium Signaling”

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PubMed1996

Calcium signals and protein tyrosine kinases are required for the induction of c-jun in Jurkat cells stimulated by the T cell-receptor complex and oxidative signals.

The regulation of c-jun plays an important role in T cell activation, proliferation, and expression of interleukin-2. In the present study, we determined whether Ca2+ signals and the activity of protein tyrosine kinases (PTKs) were required for the induction of c-jun in Jurkat cells stimulated with cross-linked anti-T cell receptor/CD3 antibodies or exposed to oxidative stress in the form of micromolar concentrations of H2O2. Jurkat cells exhibited rapid elevations in intracellular calcium [Ca2+]i levels in response to H2O2 and cross-linked anti-CD3 antibodies that mainly reflected the influx of extracellular Ca2+. The Ca2+ flux in response to oxidative signals was distinguished by an exquisite sensitivity to inhibition with Ni2+, suggesting the involvement of cation channels. PTK activity was needed for [Ca2+]i elevations in response to both oxidative and anti-CD3 signals, although H2O2 induction of [Ca2+]i increases was more resistant to inhibition by genistein than anti-CD3 [Ca2+]i responses. Both oxidative signals and anti-CD3 stimulation induced increased levels of c-jun and c-fos mRNA. The increased expression of c-jun with H2O2 was preceded by [Ca2+]i increases and accompanied by activation of c-Jun aminoterminal kinases (JNKs), as well as increased AP-1 binding activity. Induction of c-jun with oxidative signals and anti-CD3 was also shown to be crucially dependent on [Ca2+]i elevations because the chelation of [Ca2+]i with BAPTA resulted in a dose-dependent inhibition of c-jun expression. Furthermore, inhibition studies demonstrated that the optimal induction of c-jun mRNA in response to oxidative signals required PTK as well as protein kinase C (PKC). Thus, these findings suggest that both [Ca2+]i signals and the activity of PTKs are essential for the optimal expression of c-jun in response to TCR/CD3 signals and changes in redox potentials.

Antibody Formation↗
PubMedDate not supplied

Transient receptor potential channels in the kidney: calcium signaling, transport and beyond.

Multiple cationic channels with variable selectivity for Ca(2+) , K(+) and Na(+) have been identified in smooth muscle cells (SMC) as well as non-excitable cells. They control Ca(2+) store refilling and depletion, G-protein-mediated receptor activation, apoptosis and cell growth, membrane potential, intracellular pH, oxidative stress, phospholipid signaling, and other critical cell functions. A novel superfamily of divalent cation channels has been recently characterized as highly conserved heterotetramer homologues of Drosophila transient receptor potential (TRP). At least 50 members of seven major TRP channel families have been identified to date. The involvement of TRP in store-operated Ca(2+) - gating has been demonstrated in various tissues, along with intestinal and renal epithelial cell Ca(2+) and Mg(2+) transport, indicating a role in total body homeostasis of divalent cations. TRPV5-null mice display phenotypic defects including hypercalciuria and impaired bone mineral density. TRPP2 or polycystin 2 (PC2), encoded by the PKD2 gene, is an integral protein of epithelial cilia whose mutation is associated with autosomal dominant polycystic kidney disease (ADPKD). A TRPP1 (polycystin 1)-PC2 channel complex is actually implicated in the transduction of environmental signals (i.e. luminal tubular fluid flow and composition) into cellular events, such as epithelial cell growth. TRP channels can eventually play a role in the pathogenesis of arterial hypertension via direct effects on vascular smooth muscle contraction, renal blood flow, glomerular hemodynamics and the tubular handling of Ca(2+) and electrolytes.

Animals↗
PubMed1990

Characterization of a new type of variant of rat basophilic leukemia 2H3 cells presenting a different pattern of calcium signal.

We selected a new type of variant (designated 3C7) derived spontaneously from parental RBL-2H3 cells. 3C7 cells showed lower contact inhibition, anchorage dependency, and serotonin release activity than those of RBL-2H3 cells. We conclude that 3C7 cells are a transformant of RBL-2H3 cell with greater malignancy. The production of inositol bisphosphate and the release of Ca2+ from intracellular stores induced by IgE-antigen stimulation were enhanced in 3C7. Oscillation of [Ca2+]i in individual 3C7 cells was observed by a digital imaging microscopic technique. We propose that 3C7 cells are a useful model system for studies on the mechanisms of stimulus-secretion coupling and the relationships between malignant alterations and disorders of signal transduction.

Animals↗
PubMed1997

Possible involvement of pertussis toxin-sensitive G protein in hepatocyte growth factor-induced signal transduction in cultured rat hepatocytes: pertussis toxin treatment inhibits activation of phospholipid signaling, calcium oscillation, and mitogen-activated protein kinase.

Treatment of primary cultured rat hepatocytes with hepatocyte growth factor (HGF) gives rise to inositol phosphate formation, cytosolic calcium oscillation, activation of mitogen-activated protein (MAP) kinase and phospholipase D (PLD), and arachidonic acid release, leading to DNA synthesis. Pretreatment of cultured hepatocytes with pertussis toxin (PT), which is known to adenosine diphosphate-ribosylate Gi and Go guanine nucleotide -binding proteins and to inhibit their functions, partially inhibited HGF-induced [3H]thymidine incorporation in a concentration-dependent manner. These results suggest that HGF-mediated DNA synthesis of hepatocytes is partly regulated via PT-sensitive guanine nucleotide-binding protein. Therefore, the effects of PT treatment on HGF-induced signal-transduction pathways were investigated. HGF-induced MAP kinase activation and arachidonic acid release were decreased by PT treatment, whereas PLD activation was diminished by PT to the level of unstimulated control. PT also interfered with HGF-induced inositol phosphate formation and cytosolic calcium oscillation. These results suggest that both PT-sensitive and PT-insensitive pathways are involved in HGF-induced signaling.

Animals↗
PubMed1997

Development of calcium signalling mechanisms during maturation of human oocytes.

Sperm-induced Ca2+ signals mediate the events of oocyte activation at fertilization. In this study, the development of mechanisms involved in the generation of Ca2+ signals in human oocytes was investigated. The thiol reagent, thimerosal, which induces oscillations of intracellular Ca2+ ([Ca2+]i) similar to those seen during fertilization, was used to mobilize Ca2+ in in-vivo matured, immature and in-vitro matured human oocytes. There was an increase in the sensitivity to thimerosal during maturation of human oocytes, with oocytes from small antral follicles being relatively insensitive, compared with those from luteinized follicles, which displayed a large spike followed by sustained oscillations in [Ca2+]i. These oscillations were inhibited by caffeine which suggests that they were mediated by the inositol trisphosphate receptor Ca2+ release system. When immature oocytes were cultured in vitro they acquired the capacity to undergo a single large spike in [Ca2+]i, however, subsequent sustained oscillations were not observed, indicating that these oocytes failed to develop fully competent Ca2+ signalling mechanisms during culture in vitro. This finding may be a key factor in the poor developmental competence of in-vitro matured human oocytes.

Calcium↗
PubMed1993

Mechanical stimulation induces intercellular calcium signaling in bovine aortic endothelial cells.

To study the mechanism by which endothelial cells respond to mechanical forces, we used digital fluorescence microscopy to measure changes in intracellular Ca2+ concentration ([Ca2+]i) in primary cultures of bovine aortic endothelial cells in response to mechanical stimulation. Before stimulation, [Ca2+]i was stable (approximately 50-75 nM). When an individual cell within the monolayer was mechanically stimulated with a microprobe, [Ca2+]i increased in the stimulated cell and spread in the form of a wave from the site of contact to the cell edges. After a delay of approximately 1 s, nonstimulated adjacent cells showed a similar spreading rise in [Ca2+]i. This outwardly radiating [Ca2+]i wave involved progressively more distal cells to a radius of 4-6 cells. The time delay before the wave appeared in adjacent cells increased, and peak [Ca2+]i in each cell decreased with distance from the stimulated cell. In the absence of extracellular Ca2+, there was no increase in [Ca2+]i in the stimulated cell, yet a wave of increased [Ca2+]i occurred in neighboring cells as if communicated from the stimulated cell. These results indicate that endothelial cell mechanosensitivity results in increases in [Ca2+]i and that the temporospatial dynamics of intercellular Ca2+ signaling are mediated by a diffusible substance other than Ca2+.

Animals↗
PubMed1991

Calcium signal and histamine secretion induced by aggregation of immunoglobulin E receptors in rat basophilic leukemia (RBL-2H3) cells.

The changes in cytosolic Ca concentration in rat basophilic leukemia cells (RBL-2H3) were determined using a fluorescent Ca probe, fura-2, after aggregation of IgE receptors. By means of a superfusion system, both histamine secretion and changes in cytosolic Ca concentration were determined simultaneously. In addition, the microscopic observation revealed the oscillatory Ca signal after stimulation with an antigen.

Animals↗
PubMed1990

Inositol phosphate formation and its relationship to calcium signaling.

The activation of a variety of cell surface receptors results in a biphasic increase in the cytoplasmic Ca2+ concentration due to the release or mobilization of Ca2+ from intracellular stores and to the entry of Ca2+ from the extracellular space. It is well established that phosphatidylinositol 4,5-bisphosphate hydrolysis is responsible for the changes in Ca2+ homeostasis. Stimulation of Ca2(+)-mobilizing receptors also results in the phospholipase C-catalyzed hydrolysis of the minor plasma membrane phospholipid, phosphatidylinositol 4,5-bisphosphate, with the concomitant formation of inositol (1,4,5) trisphosphate [1,4,5)IP3) and diacylglycerol. Analogous to the adenylyl cyclase signaling system, receptor-mediated stimulation of phospholipase C also appears to be mediated by one or more intermediary guanine nucleotide-dependent regulatory proteins. There is strong evidence that (1,4,5)IP3 stimulates Ca2+ release from intracellular stores. The Ca2(+)-releasing actions of (1,4,5)IP3 are terminated by its metabolism through two distinct pathways. (1,4,5)IP3 is dephosphorylated by a 5-phosphatase to inositol (1,4) bisphosphate; alternatively, (1,4,5)IP3 can be phosphorylated to inositol (1,3,4,5) tetrakisphosphate by a 3-kinase. Whereas the mechanism of Ca2+ mobilization is understood, the precise mechanisms involved in Ca2+ entry are not known. A recent proposal that (1,4,5)IP3 secondarily elicits Ca2+ entry by emptying an intracellular Ca2+ pool will be considered. This review summarizes our current understanding of the mechanisms by which inositol phosphates regulate cytoplasmic Ca2+ concentrations.

Animals↗
PubMed2000

Inhibition of calcium signaling in terminal and soma of carp retinal bipolar cells by GABA.

AIM: To investigate the effect of activation of gamma-aminobutyric acid (GABA) receptors on high K(+)-evoked Ca2+ signaling in the terminal and soma of carp retinal ON-type bipolar cells. METHODS: Freshly dissociated carp retinal cells were loaded with fluo-3AM and then the fluorescence measurements were performed on a confocal laser-scanning microscope. RESULTS: Ca2+ signaling evoked by high K+ 35 mmol/L was completely suppressed in both the terminal and soma of bipolar cells by GABA 100 mumol/L. However, different results were found in the terminal and soma when only one subtype of GABA receptors was activated. While activation of either GABAA or GABAC receptors totally suppressed Ca2+ signaling in the soma, a gradual elevation of [Ca2+]i appeared in the terminal. GABA 10 mumol/L could also completely suppress Ca2+ signaling in the soma, but could only partially reduce Ca2+ signaling in the terminal. CONCLUSION: Activation of both GABAA and GABAC receptors could completely inhibit high K(+)-evoked Ca2+ signaling in the terminal and soma of carp retinal ON-type bipolar cells. While activation of either GABAA or GABAC receptors alone still totally suppressed Ca2+ signaling in the soma, a gradual elevation of [Ca2+]i appeared in the terminal, which may be due to desensitization of GABA receptors.

Animals↗
PubMed1992

Calcium signals in growth factor signal transduction.

There is a substantial amount of information which has been obtained concerning the effects of growth factors on [Ca2+]i in proliferating cells. A number of different mitogens are known to induce elevations in [Ca2+]i and some characterization of the Ca2+ response to different classes of mitogens has been obtained. In addition, much is known about whether the Ca2+ response to a particular growth factor occurs as the result of an influx of external Ca2+ or a mobilization of internal Ca2+ stores. In addition, a considerable amount of information is available on the mechanism by which the Ins(1,4,5)P3-sensitive internal Ca2+ store takes up and releases Ca2+. However, there is still a large deficiency in our information concerning other Ca2+ stores in proliferating cells as well as in our knowledge of the mechanisms for regulating Ca2+ entry pathways. Much more data addressing these issues exists for other types of agonist-stimulated cells, and we have discussed much of it in this review article. While the wealth of data in nonproliferating cells provides some indications of what mechanisms might be involved in the growth factor-induced changes in [Ca2+]i, it is clear that much work must be done in proliferating cells to fully understand how external factors such as growth factors control [Ca2+]i. In addition, much work remains to be done in identifying the mechanisms for the internal control of [Ca2+]i as cells move through the cell cycle and in identifying the role that these changes in [Ca2+]i may play throughout the cell cycle.

Animals↗
PubMed1994

Multiple calcium signaling pathways in Mardin-Darby canine kidney cells.

Effects of various receptor agonists on cytoplasmic Ca2+ concentration ([Ca2+]i) were examined in fura-2-loaded Mardin-Darby canine kidney (MDCK) monolayer cells. Carbachol (100 microM) increased [Ca2+]i which slightly declined to a sustained increase in [Ca2+]i. On the other hand, [Ca2+]i elevated by 100 nM bradykinin (BK) declined to a resting level of [Ca2+]i even in the presence of BK. After washout of BK, the subsequent addition of a higher concentration of BK (1 microM) caused a smaller increase in [Ca2+]i than that induced by 100 nM BK. Isoproterenol (100 microM) did not increase [Ca2+]i by itself but caused an transient increase in [Ca2+]i in the presence of 1 mM isobutyl-methylxanthine (IBMX). Prostaglandin E1 (1 microM) resulted in a slight increase in [Ca2+]i which was potentiatedin the presence of 1 mM IBMX. The microsomal Ca(2+)-ATPase inhibitor thapsigargin (100 nM) caused a sustained increase in [Ca2+]i. These results suggest that MDCK cells have multiple Ca2+ signaling pathways which may regulate epithelial cell functions.

1-Methyl-3-isobutylxanthine↗
PubMed2005

Acrolein induces Hsp72 via both PKCdelta/JNK and calcium signaling pathways in human umbilical vein endothelial cells.

Acrolein is a highly electrophilic alpha,beta-unsaturated aldehydes to which humans are exposed in a variety of environment situations and is also a product of lipid peroxidation. Increased levels of unsaturated aldehydes play an important role in the pathogenesis of a number of human diseases such as Alzheimer's disease, atherosclerosis and diabetes. A number of studies have reported that acrolein evokes downstream signaling via an elevation in cellular oxidative stress. Here, we report that low concentrations of acrolein induce Hsp72 in human umbilical vein endothelial cells (HUVEC) and that both the PKCdelta/JNK pathway and calcium pathway were involved in the induction. The findings confirm that the production of reactive oxygen species (ROS) is not directly involved in the pathway. The induction of Hsp72 was not observed in other cells such as smooth muscle cells (SMC) or COS-1 cells. The results suggest that HUVEC have a unique defense system against cell damage by acrolein in which Hsp72 is induced via activation of both the PKCd/JNK and the calcium pathway.

Acrolein↗
PubMed1994

Modulation of calcium signaling and LH secretion by progesterone in pituitary gonadotrophs and clonal pituitary cells.

In estradiol-treated pituitary cells, progesterone enhances gonadotropin-releasing hormone (GnRH)-induced LH secretion from cultured rat pituitary cells during short-term treatment but attenuates this response during prolonged treatment. In the present study, the effects of gonadal steroids on GnRH-induced cytoplasmic calcium ([Ca2+]i) responses in gonadotrophs were analyzed in rat pituitary cells and immortalized (alpha T3-1) murine gonadotrophs. Ca2+ responses were measured in cell suspensions and single gonadotrophs, loaded with Fura-2 or Indo-1, respectively, and pretreated for 48 h with 1 nM estradiol with or without 100 nM progesterone, or for 48 h with 1 nM estradiol and then for 3 h with 100 nM progesterone. In cells of the alpha T3-1 gonadotroph lineage, GnRH elicited biphasic Ca2+ signals composed of an initial peak response followed by a prolonged plateau phase. The amplitudes of both the extracellular Ca(2+)-independent spike phase and the extracellular Ca(2+)-dependent plateau phase were enhanced or inhibited by short- or long-term progesterone treatment, respectively. In single pituitary gonadotrophs, GnRH (0.5 nM) elicited oscillatory responses due to intermittent release and uptake of Ca2+ from intracellular stores. Treatment with progesterone shifted the oscillatory signal toward biphasic (3 h) or subthreshold (48 h) response profiles, revealing a steroid-induced change in the pattern of Ca2+ mobilization. In addition to these agonist-induced responses, the transient [Ca2+]i responses of pituitary cells and individual gonadotrophs to high K+ were enhanced or inhibited after short- or long-term progesterone treatment, respectively. These actions were correlated with the effects of progesterone on K(+)-induced LH secretion. The [Ca2+]i and LH secretory responses to phorbol ester treatment were also enhanced by short-term exposure of the cells to progesterone. The results demonstrate that the stimulatory and inhibitory effects of progesterone on agonist-induced Ca2+ signaling result from changes in Ca2+ mobilization and entry, and contribute to the modulatory actions of the steroid on GnRH-induced LH secretion.

Animals↗
PubMed1995

Calbindin-D28K facilitates cytosolic calcium diffusion without interfering with calcium signaling.

The role of calbindin-D28K, in transcellular Ca2+ transport and Ca2+ signaling in rabbit cortical collecting system was investigated. Rabbit kidney connecting tubules and cortical collecting ducts, hereafter referred to as cortical collecting system, were isolated by immunodissection and cultured to confluence on permeable filters and glass coverslips. Calbindin-D28K was present in the cytosol of principal cells, but was absent from the intercalated cells. 1,25(OH)2D3 (48 h, 10(-7) M) significantly increased cellular calbindin-D28K levels (194 +/- 15%) and stimulated transcellular Ca2+ transport (41 +/- 3%). This stimulatory effect could be fully mimicked by the endogenous Ca2+ chelator, BAPTA (30 microM BAPTA/AM), which suggests that the presence of Ca2+ chelators alone is sufficient to enhance transcellular Ca2+ transport. Stimulation of Ca2+ transport was not accompanied by a rise in [Ca2+]i. Isosmotic replacement of extracellular Na+ ([Na+]o) for N-methylglucamine (NMG) generated oscillations in [Ca2+]i in individual cells of the monolayer. The functional parameters of these oscillations such as frequency of spiking, resting [Ca2+]i, increase in [Ca2+]i and percentage of responding cells, were not affected by the level of calbindin-D28K. In contrast, loading the cells with BAPTA abruptly stopped these [Ca2+]i oscillations. This suggests that the kinetics of Ca2+ binding by calbindin-D28K are slow relative to the initiation of the [Ca2+]i rise, so that calbindin-D28K, unlike BAPTA, is unable to reduce [Ca2+]i rapidly enough to prevent the initiation of Ca(2+)-induced Ca2+ release.

Animals↗
PubMed1997

Calreticulin is essential for integrin-mediated calcium signalling and cell adhesion.

Integrins are important mediators of cell adhesion to extracellular ligands and can transduce biochemical signals both into and out of cells. The cytoplasmic domains of integrins interact with several structural and signalling proteins and consequently participate in the regulation of cell shape, motility, growth and differentiation. It has been shown that calreticulin associates with the cytoplasmic domains of integrin alpha-subunits and that this interaction can influence integrin-mediated cell adhesion to extracellular matrix. We have now developed calreticulin-deficient embryonic stem (ES) cells and isolated embryonic fibroblasts from calreticulin mutant mice. We find that in both cell types integrin-mediated adhesion is severely impaired, although integrin expression is unaltered. Expression of recombinant calreticulin in double knockout ES cells by complementary DNA transfection rescued integrin-mediated adhesion. In wild-type cells, engagement of surface integrins induced a transient elevation in cytosolic calcium concentration owing to influx of extracellular calcium. This calcium transient was absent in calreticulin-deficient cells. In contrast, the amount of calcium in endomembrane stores, which is sensitive to both inositol 1,4,5-trisphosphate and thapsigargin, was indistinguishable in the two cell types. Our results indicate that calreticulin is an essential modulator both of integrin adhesive functions and integrin-initiated signalling, but that it may not play a significant role in the storage of luminal calcium.

Animals↗