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Results for “Calcium Signaling”

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PubMed2004

Factor Xa stimulates fibroblast procollagen production, proliferation, and calcium signaling via PAR1 activation.

Fibroblast proliferation and procollagen production are central features of tissue repair and fibrosis. In addition to its role in blood clotting, the coagulation cascade proteinase thrombin can contribute to tissue repair by stimulating fibroblasts via proteolytic activation of proteinase-activated receptor-1 (PAR1). During hemostasis, the coagulation cascade proteinase factor X is converted into factor Xa. We have previously shown that factor Xa upregulates fibroblast proliferation via production of autocrine PDGF. In this study, we further examined the effects of factor Xa on fibroblast function and aimed to identify its signaling receptor. We showed that factor Xa stimulates procollagen promoter activity and protein production by human and mouse fibroblasts. This effect was independent of PDGF and thrombin production, but dependent on factor Xa proteolytic activity. We also showed that PAR1-deficient mouse fibroblasts did not upregulate procollagen production, mobilize cytosolic calcium, or proliferate in response to factor Xa. Desensitization techniques and PAR1-specific agonists and inhibitors were used to demonstrate that PAR1 mediates factor Xa signaling in human fibroblasts. This is the first report that factor Xa stimulates extracellular matrix production. In contrast with endothelial cells and vascular smooth muscle cells, fibroblasts appear to be the only cell type in which the effects of factor Xa are mediated mainly via PAR1 and not PAR2. These findings are critical for our understanding of tissue repair and fibrotic mechanisms, and for the design of novel approaches to inhibit the profibrotic effects of the coagulation cascade without compromising blood hemostasis.

Animals↗
PubMed2005

A molecular dissection of lymphocyte unresponsiveness induced by sustained calcium signalling.

In lymphocytes, integration of Ca2+ and other signalling pathways results in productive activation, while unopposed Ca2+ signalling leads to decreased responsiveness to subsequent stimulation (anergy). The Ca(2+)-regulated transcription factor NFAT has an integral role in both aspects of lymphocyte function. NFAT cooperates with the transcription factor AP-1 (Fos/Jun) to up-regulate genes involved in productive activation of lymphocytes. However, in the absence of AP-1, NFAT imposes an opposing genetic programme that leads to lymphocyte anergy. Anergy is implemented at least partly through proteolytic degradation of the key signalling proteins PKCtheta and PLCgamma1. Sustained Ca(2+)-calcineurin signalling increases mRNA and protein levels of the E3 ubiquitin ligases Itch, CblB and Grail and induces expression of Tsg1O1, the ubiquitin-binding component of the ESCRT1 endosomal sorting complex. Subsequent stimulation or homotypic cell adhesion promotes membrane translocation of Itch and the related protein Nedd4, resulting in PKCtheta and PLCgamma1 degradation. T cells from Itch- and CblB-deficient mice are resistant to anergy induction. Anergic T cells show impaired calcium mobilization after TCR triggering and are unable to maintain a mature immunological synapse. Thus Ca(2+)-calcineurin-NFAT signalling links gene transcription to a multi-step programme that leads to impaired signal transduction in anergic T cells.

Calcium Signaling↗
PubMed1994

The inositol phosphate-calcium signalling system in lacrimal gland cells.

From the above discussion, it is clear that the regulation of Ca2+ signalling in exocrine cells is a complex process involving activation of both intracellular Ca2+ release as well as the entry of Ca2+ across the plasma membrane. A poorly understood mechanism links these two phases of Ca2+ signalling thereby providing both rapid as well as sustained signals for the initiation and maintenance of appropriate exocrine responses. Further work is needed to better understand the mechanisms controlling this important and ubiquitous signalling system.

Animals↗
PubMed1997

Target cell-induced calcium signals in human natural killer leukemia cells as revealed by confocal fluorescence microscopy.

The target cell-induced calcium response in natural killer (NK) cells was examined using indo-1 (a ratiometric fluorochrome), a newly developed video-rate ultraviolet laser-scanning confocal microscope system, and a human NK leukemia cell line, YTN. Susceptible target cells (JY cells), but not unsusceptible target cells (K562 cells), increased the intracellular calcium concentration ([Ca]i) in almost all indo-1-loaded YTN cells with a lag time, although the kinetics of increase in [Ca]i differed in individual YTN cells. The increase in [Ca]i was completely blocked by 2 mM EGTA and partially (around 50%) blocked by 10 microM nicardipine, the extents of inhibition of calcium response correlating well with those of inhibition of cytotoxic activity. Thus, the calcium response in YTN cells observed in this study may constitute a critical step in the manifestation of cytotoxic activity.

Biological Transport↗
PubMed2000

Microheterogeneity of calcium signalling in dendrites.

Transient changes in the intracellular concentration of free Ca2+ ([Ca2+]i) originating from voltage- or ligand-gated influx and by ligand- or Ca2+-gated release from intracellular stores, trigger or modulate many fundamental neuronal processes, including neurotransmitter release and synaptic plasticity. Of the intracellular compartments involved in Ca2+ clearance, the endoplasmic reticulum (ER) has received the most attention because it expresses Ca2+ pumps and Ca2+ channels, thus endowing it with the potential to act as both an intracellular calcium sink and store. We review here our ongoing work on the role of calcium sequestration into, and release from, ER cisterns and the role that this plays in the generation and termination of free [Ca2+]i transients in dendrites of pyramidal neurons in hippocampal slices during and after synaptic activity. These studies have been approached by combining parallel microfluorometric measurements of free cytosolic [Ca2+]i transients with energy-dispersive X-ray microanalytical measurements of total Ca content within specific dendritic compartments at the electron microscopy level. Our observations support the emerging realization that specific subsets of dendritic ER cisterns provide spatial and temporal microheterogeneity of Ca2+ signalling, acting not only as a major intracellular Ca sink involved in active clearance mechanisms after voltage- and ligand-gated Ca2+ influx, but also as an intracellular Ca2+ source that can be mobilized by a signal cascade originating at activated synapses.

Animals↗
PubMed1998

Calcium currents and calcium signaling in rod bipolar cells of rat retinal slices.

Combined electrophysiological and imaging techniques were used to study calcium currents (ICa) and their sites of origin at rod bipolar cells in rat retinal slices. We report here for the first time the successful whole-cell patch-clamp recording from presynaptic boutons that were compared with somatic recordings. TTX-resistant inward currents were elicited in response to depolarization. The kinetic and pharmacological properties of ICa were very similar for recordings obtained from the soma and the presynaptic terminals. ICa activated maximally between -30 and -20 mV was enhanced by Bay K 8644 and was blocked by isradipine and nifedipine. Peak amplitude and time to peak were -31.3 +/- 1.2 pA and 3.2 +/- 0.2 msec with somatic recordings (n = 54), whereas the corresponding values were -31.6 +/- 6.1 pA and 3.2 +/- 0.7 msec in recordings obtained directly from terminals (n = 6). ICa showed little inactivation during sustained depolarizations. No T-type ICa was observed with depolarizations from -90 mV. Concomitant with Ca2+ entry, depolarization induced the appearance of transient outward currents that resembled IPSCs and were blocked by GABA and glycine receptor antagonists, suggesting that they arise from activation of amacrine feedback synapses. Upon depolarization, intracellular Ca2+ ([Ca2+]i) rises were restricted to the presynaptic terminals with no somatic or axonal changes and were linearly dependent on pulse duration when using a low-affinity Ca2+ indicator. In cone bipolar cells, ICa inactivated markedly, and [Ca2+]i rises occurred in the axon, as well as in the presynaptic terminals.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1986

Regulation of the calcium signal by calmodulin.

Stimulus-response coupling mediated by calmodulin involves several steps: a transitory increase in calcium concentration from 0.1 to 10 microM, induced by external stimuli; interaction of calcium with calmodulin, accompanied by stepwise structural transitions; the coordinated interaction with and activation of the many calmodulin-regulated enzymes and proteins. The binding of calcium to calmodulin is a cooperative and selective process that is modulated by magnesium. At physiological ionic strength, and only in the presence of magnesium, a large difference is seen between the affinities of sites III and IV (0.09 X 10(6) M-1) and sites I and II (0.0007 X 10(6) M-1) for calcium. This difference, together with the positive cooperativity previously observed, explains the stepwise conformational changes induced by calcium. The interaction of calmodulin with its target proteins requires the integrity of different portions of the calmodulin molecule. Calmodulin-regulated enzymes can be divided into three classes according to their abilities to bind with and to be activated by calmodulin fragments: enzymes which are activated by the C-terminal fragment, such as the Ca2+-ATPase and phosphorylase kinase; enzymes which require both halves of the molecule, such as cyclic AMP phosphodiesterase and myosin light chain kinase; and enzymes whose interaction with calmodulin fragments is too weak to be detected by activation, such as calcineurin and the multiprotein kinase. Thus different enzymes may be activated by different calmodulin conformers and the stepwise changes exhibited by calmodulin at different calcium levels can be used to regulate different metabolic pathways.

Animals↗
PubMed2004

Learning about cardiac calcium signaling from genetic engineering.

Genetic engineering has already provided critical data on the Ca-induced Ca(2+) release (CICR) hypothesis issues and promises even greater future insights. The two approaches employed thus far are (1) the construction of transgenic animal models with deletion or overexpression of Ca(2+) signaling proteins, and (2) direct structure-function studies of these proteins in artificial systems. In our laboratory both approaches have provided some insight into molecular modulation of CICR and the pathophysiology arising from the deletion or overactivity of these proteins. Probing the cytoplasmic segments of the carboxyl c-terminal tail of Ca(2+) channel, we identified two calcium sensing and calmodulin binding domains (LA and K) that have been implicated in Ca(2+)-induced inactivation of Ca(2+) channels. Introducing these peptides into atrial myocytes, where a large fraction of Ca(2+) release sites are unassociated with the dihydropyridine receptors (DHPRs) (no t-tubules), suggests that LA, but not K motif, increases the sensitivity of RyRs to Ca(2+), is responsible for the higher frequency of Ca(2+) sparks in the peripheral sites, and provides for the voltage dependence of CICR. Genetic overexpression or deletion of the primary proteins of the Ca(2+) signaling cascade also provides supportive evidence for the Ca(2+) current (I(Ca))-gated CICR mechanism, generates some novel and unexpected cardiac phenotypes in transgenic mice, and suggests that Ca(2+) signaling defects can trigger compensatory molecular mechanisms that underlie the observed cardiac phenotype and pathophysiology.

Animals↗
PubMed2001

[Cardiac hypertrophy and calcium signaling].

Numerous studies have implicated intracellular Ca(2+) as a signal for cardiac hypertrophy. It has recently been reported that the calcium-dependent phosphatase calcineurin plays a critical role in the development of cardiac hypertrophy. It is also reported that cyclosporin A and FK506, calcineurin inhibitors, inhibit the development of cardiac hypertrophy. Inhibiting the calcineurin activity may be of potential benefit for prevention of cardiac hypertrophy and heart failure.

English Abstract↗
PubMed1999

Marked temperature dependence of the platelet calcium signal induced by human von Willebrand factor.

Interaction of von Willebrand factor (vWF) with the platelet is essential to hemostasis when vascular injury occurs. This interaction elevates the intracellular free calcium concentration ([Ca2+]i) and promotes platelet activation. The present study investigated the temperature dependence of vWF-induced [Ca2+]i signaling in human platelets. The influence of temperature can provide invaluable insight into the underlying mechanism. Platelet [Ca2+]i was monitored with Fura-PE3. Ristocetin-mediated binding of vWF induced a transient platelet [Ca2+]i increase at 37 degrees C, but no response at lower temperatures (20 degrees C to 25 degrees C). This temperature dependence could not be attributed to a reduction in vWF binding, as ristocetin-mediated platelet aggregation and agglutination were essentially unaffected by temperature. Most other platelet agonists (U-46619, alpha-thrombin, and adenosine 5'-diphosphate [ADP]) induced a [Ca2+]i signal whose amplitude did not diminish at lower temperatures. The [Ca2+]i signal in response to arachidonic acid, however, showed similar temperature dependence to that seen with vWF. Assessment of thromboxane A2 production showed a strong temperature dependence for metabolism of arachidonic acid by the cyclo-oxygenase pathway. vWF induced thromboxane A2 production in the platelet. Aspirin treatment abolished the vWF-induced [Ca2+]i signal. These observations suggest that release of arachidonic acid and its conversion to thromboxane A2 play a central role in vWF-mediated [Ca2+]i signaling in the platelet at physiological temperatures.

Blood Platelets↗
PubMed2002

Calcium signaling at single mossy fiber presynaptic terminals in the rat hippocampus.

We investigated internal Ca(2+) release at mossy fiber synapses on CA3 pyramidal neurons (mossy fiber terminals, MFTs) in the hippocampus. Presynaptic Ca(2+) influx was induced by giving a brief train of 20 stimuli at 100 Hz to the mossy fiber pathway. Using Ca(2+) imaging techniques, we recorded the Ca(2+) response as DeltaF/F, which increased rapidly with stimulation, but was often accompanied by a delayed peak that occurred after the train. The rise in presynaptic [Ca(2+)] could be completely blocked by application of 400 microM Cd(2+). Furthermore, the evoked Ca(2+) signals were reduced by group II mGluR agonists. Under the same experimental conditions, we investigated the effects of several agents on MFTs that disrupt regulation of intracellular Ca(2+) stores resulting in depletion of internal Ca(2+). We found that ryanodine, cyclopiazonic acid, thapsigargin, and ruthenium red all decreased both the early and the delayed increase in the Ca(2+) signals. We applied D,L-2-amino-5-phosphonovaleric acid (D,L-APV; 50 microM) and 6,7-Dinitroquinoxaline-2,3-dione (DNQX; 20 microM) to exclude the action of N-methyl-D-aspartate (NMDA) and non-NMDA receptors. Experiments with alternative lower affinity indicators for Ca(2+) (fura-2FF and calcium green-2) and the transient K(+) channel blocker, 4-aminopyridine were performed to control for the possible saturation of fura-2. Taken together, these results strongly support the hypothesis that the recorded terminals were from the mossy fibers of the dentate gyrus and suggest that a portion of the presynaptic Ca(2+) signal in response to brief trains of stimuli is due to release of Ca(2+) from internal stores.

2-Amino-5-phosphonovalerate↗
PubMed2005

Pure albumin is a potent trigger of calcium signalling and proliferation in microglia but not macrophages or astrocytes.

Microglial activation is implicated in the neurotoxicity of neurodegenerative diseases. Raised intracerebral levels of albumin are associated with the pathology of Alzheimer's disease, multiple sclerosis, and stroke where blood-brain barrier damage is evident. We report here that treatment of primary cultured microglia and the N9 microglial cell line with pure albumin, or albumin in which fatty acids and immunoglobulins remain attached (fraction V), induced a rise in intracellular calcium. This rise in intracellular calcium was mediated via Src tyrosine kinase and phospholipase C. The albumin-induced calcium response was coupled to microglial proliferation, which was prevented by BAPTA, U73122 or PP2 but not mimicked by thapsigargin. In contrast, peritoneal macrophages were resistant to albumin- or fraction V-induced calcium responses and proliferation, whilst primary cultured astrocytes or the TSA-3 astrocyte cell line were responsive to fraction V albumin but not pure albumin. Furthermore, cerebellar granule neurones did not respond to albumin. These data suggest that albumin may play a role in microglial activation in pathological situations involving blood-brain barrier impairment, and that the specific responses of microglia to albumin allow a distinction to be made between the signalling responses of microglia, blood-borne macrophages, astrocytes and neurones.

Albumins↗
PubMed2004

Regulation of calcium signalling and gene expression by glutathione.

The glutathione redox couple is an information-rich redox buffer that interacts with numerous cellular components. To explore the role of glutathione in redox signalling, leaf contents were increased either chemically, by feeding reduced glutathione (GSH), or genetically, by over-expressing the first enzyme of the GSH biosynthetic pathway, gamma-glutamylcysteine synthetase (gamma-ECS). Leaf discs were also fed glutathione disulphide (GSSG), leading to increases in both GSH and GSSG. The effects of increases in GSH were compared with non-specific changes in leaf thiol status induced by feeding dithiothreitol (DTT) or the monothiol beta-mercaptoethanol (beta-ME). Photosynthesis measurements showed that none of the feeding treatments greatly disrupted leaf physiology. Transgenic plants expressing aequorin were used to analyse calcium signatures during the feeding treatments. Calcium release occurred soon after the onset of GSH or GSSG feeding, but was unaffected by DTT or beta-ME. Pathogenesis-related protein 1 (PR-1) was induced both in the gamma-ECS overexpressors and by feeding GSH, but not GSSG. Feeding DTT also induced PR-1. Key transcripts encoding antioxidative enzymes were much less affected, although glutathione synthetase was suppressed by feeding thiols or GSSG. It is concluded that modulation of glutathione contents transmits information through diverse signalling mechanisms, including (i) the establishment of an appropriate redox potential for thiol/disulphide exchange and (ii) the release of calcium to the cytosol.

Calcium Signaling↗
PubMed2005

The anti-apoptotic effects of nordihydroguaiaretic acid: inhibition of cPLA(2) activation during TNF-induced apoptosis arises from inhibition of calcium signaling.

Nordihydroguaiaretic acid (NDGA) is a plant lignan produced by Larrea tridentata, the creosote bush of the American southwest. In this report we examine the mechanism underlying the ability of NDGA to inhibit TNF-induced apoptosis. Our results show that NDGA blocks many key indicators of apoptosis. Caspase cleavage, mitochondrial inactivation, externalization of phosphatidyl serine, and (51)Cr-release were all blocked by low micromolar concentrations of NDGA. NDGA also inhibited the cPLA(2)-dependent release of (3)H-arachidonic acid. We investigated this activity and found that NDGA prevented the rise in intracellular calcium necessary for the apoptotic activation of cPLA(2). On the other hand, NDGA did not interfere with the TNF-induced phosphorylation of cPLA(2), indicating that NDGA does not block all TNF-dependent signaling. Finally, we asked whether the anti-apoptotic effect of NDGA could be attributed to its anti-oxidant activity. Comparison with the effects of butylated hydroxyanisole (BHA) did not completely support this hypothesis. While BHA strongly inhibited caspase activation and partially blocked the release of (51)Cr, it was unable to significantly block the calcium response or the release of (3)H-arachidonic acid associated with TNF-induced apoptosis. The anti-oxidant activity of NDGA may, therefore, explain some but not all of its anti-apoptotic activity.

Animals↗