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PubMed2005

Intracellular-free calcium dynamics and F-actin alteration in the formation of macrophage foam cells.

The formation of macrophage foam cells, which is the key event in atherosclerosis, occurs by the uptake of oxidized low-density lipoprotein (Ox-LDL) via the scavenger receptor (CD36) pathway. Ca(2+) plays an important role in atherosclerosis. However, in the spatiotemporal view, the correlation between kinetic changes of intracellular-free calcium ([Ca(2+)](i)) and the cellular dysfunctions in the formation of macrophage foam cells has not yet been studied in detail. By the use of confocal laser scanning microscope and flow cytometer, we have detected Ca(2+) dynamics, the assembly of F-actin, and the expression of CD36 under the exposure of U937-derived macrophages to Ox-LDL. The uptake of Ox-LDL significantly increased [Ca(2+)](i) in U937-derived macrophages in both acute and chronic treatments (P<0.01). In particular, the increases of the induced [Ca(2+)](i) were different in the presence or absence of extracellular Ca(2+) under acute exposure. A time-dependent rise in F-actin assembly and CD36 expression at 12 and 24h was induced, respectively, by Ox-LDL. The spatiotemporal increases of [Ca(2+)](i) induced by Ox-LDL probably have the key effect on the early phrase in the formation of macrophage foam cells.

Actins↗
PubMed1994

Depression of calcium dynamics in cardiac myocytes--a common mechanism of halogenated hydrocarbon anesthetics and solvents.

Individual halogenated hydrocarbons (HC) have recently been demonstrated to depress Ca2+ dynamics in cardiomyocytes during excitation-contraction coupling. In the present study, eight widely used HC were systematically compared for their effects on Ca2+ dynamics in neonatal rat cardiomyocytes by means of spectrofluorometric analysis of fura-2-Ca(2+)-binding. Cells were exposed to dichloromethane (DCM), dichloroethane (DCE), 1,1,2-trichloroethane (112-TCE), trichloroethylene (TRI), halothane (HAL), 1,1,1-trichloroethane (111-TCE), perchloroethylene (PER), or pentachlorethane (PCE) in an environmentally controlled chamber. All HC tested decreased the height of electrically induced cytosolic free Ca2+ ([Ca2+]i) transients in a concentration-dependent and reversible manner (IC50 0.15-18.06 mM) without significant effects on diastolic [Ca2+]i. The increase in [Ca2+]i induced by depolarization with 90 mM KCl was inhibited to a lesser degree. Investigations with thapsigargin (100 nM) and ryanodine (1 microM)-inhibitors of Ca2+ release from the sarcoplasmic reticulum-provided evidence that the tonic Ca2+ response after KCl depolarization depends mainly on sarcolemmal Ca2+ influx. The potency of the eight HC to inhibit Ca2+ dynamics in cardiomyocytes correlated with their octanol/water partition coefficients. Results support the hypothesis that alteration of Ca2+ dynamics in cardiomyocytes is a common mechanism of cardiotoxic HC actions.

Anesthetics↗
PubMed1996

Calcium dynamics in cardiac myocytes as a target of dichloromethane cardiotoxicity.

The purpose of the present study was to determine if cardiac actions of dichloromethane (DCM) in vivo correlate with in vitro alterations of Ca2+ dynamics in cardiac myocytes. Neonatal rat ventricular myocytes were obtained from 2- to 4-day-old rats, and electrically induced fluctuations of cytosolic free Ca2+ concentration ([Ca2+]i) in single cardiomyocytes were investigated using spectrofluorometric analysis of fura-2-[Ca2+]i binding. In cultured myocytes, cumulative exposure to 0.64-40.96 mM DCM resulted in a concentration-dependent and reversible decrease in the magnitude of [Ca2+]i transients with IC10 and IC50 values of 7.98 and 18.82 mM, respectively. Total inhibition of [Ca2+]i transients and cessation of beating were observed at 40.96 mM DCM. Suffusion with DCM for 40 min did not cause morphological alterations of the myocytes. In a urethane-anesthetized rat model, left ventricular pressure was measured by introducing a tip catheter via the carotid artery into the left ventricle, the ECG was recorded by two needle electrodes applied subcutaneously to the chest wall, and arterial pressure was measured via the femoral artery. Oral administration of 3.1-12.4 mmol DCM/kg resulted in DCM blood concentrations between 1.0 and 1.6 mM, accompanied by a dose-dependent decrease in contractile force and heart rate without influencing blood pressure and ECG tracings. Moreover, DCM treatment provided significant protection against arrhythmia development due to CaCl2-infusion. In spite of the slight discrepancy between DCM blood concentrations and in vitro concentrations of DCM for [Ca2+]i transient inhibition, present data are consistent with the view that cardiac effects after DCM exposure are mediated by alterations of Ca2+ dynamics during excitation-contraction coupling.

Anesthesia↗
PubMed2006

ERK binds, phosphorylates InsP3 type 1 receptor and regulates intracellular calcium dynamics in DT40 cells.

Modulation on the duration of intracellular Ca(2+) transients is essential for B-cell activation. We have previously shown that extracellular-signal-regulated kinase (ERK) can phosphorylate inositol 1,4,5-trisphosphate receptor type 1 (IP(3)R1) at serine 436 and regulate its calcium channel activity. Here we investigate the potential physiological interaction between ERK and IP(3)R1 using chicken DT40 B-cell line in which different mutants are expressed. The interaction between ERK and IP(3)R1 is confirmed by co-immunoprecipitation and fluorescence resonance energy transfer (FRET) assays. This constitutive interaction is independent of either ERK kinase activation or IP(3)R1 phosphorylation status. Back phosphorylation analysis further shows that type 1 IP(3)R (IP(3)R1) is phosphorylated by ERK in anti-IgM-activated DT40 cells. Finally, our data show that the phosphorylation of Ser 436 in the IP(3)-binding domain of IP(3)R1 leads to less Ca(2+) release from endoplasmic reticulum (ER) microsomes and accelerates the declining of calcium increase in DT40 cells in response to anti-IgM stimulation.

Animals↗
PubMed1988

Effect of epinephrine on rapid ADP-induced aggregation, protein phosphorylation, and cytoplasmic calcium dynamics of platelets: a quenched-flow study.

We have used a general quenched-flow approach to study platelet function as early as 0.3 seconds after stimulation with a low concentration of adenosine 5'-diphosphate (ADP) (0.5 mumol/L), epinephrine (15 mumol/L), or a combination of the two. Compared with ADP alone, the combination nearly doubled the rate of aggregation as measured by the loss of single particles. Our aim was to determine whether the aggregation, protein phosphorylation, and cytoplasmic calcium responses to this potentiating combination of ADP and epinephrine were analogous to those caused by a maximal concentration of ADP (10 mumol/L) and also to determine whether cyclooxygenase was involved in this potentiation. Phosphorylation of myosin light chain (MLC) and the 47 kd protein were analyzed during the first 5 seconds of platelet response and were related to the progress of aggregation. Unlike aggregation, ADP-induced phosphorylations of both MLC and the 47 kd protein were inhibited rather than potentiated by epinephrine. Pretreatment of the platelets with indomethacin did not affect aggregation or MLC phosphorylation, but increased 47 kd phosphorylation at 0.6 seconds and eliminated it at 3 seconds. Cytoplasmic free calcium ([Ca2+]i) of indo-1-loaded platelets were monitored with our continuous-flow fluorescence approach. Although epinephrine itself did not change [Ca2+]i, it potentiated the [Ca2+]i rise induced by a low dose of ADP. A comparison of these results with platelet activation caused by 10 mumol/L ADP indicates that MLC and 47 kd phosphorylations are not correlated with [Ca2+]i dynamics and are not required or directly involved in platelet aggregation.

Adenosine Diphosphate↗
PubMed1999

Differential influences of gender and physiological status on calcium dynamics and prolactin gene expression in rat mammotropes.

The rate of prolactin (PRL) secretion is influenced by the gender and physiological state of an animal, but little is known about the mechanisms involved. In the present study, we assessed possible contributions of Ca2+ dynamics and PRL gene expression to these differences. This was accomplished by monitoring spontaneous [Ca2+]i changes and PRL promotor-driven reporter activity in pituitary cultures derived from rats comprising a broad spectrum of PRL secretory capacities: male, cycling female, and lactating rats. We found that Ca2+ oscillatory activity exhibited a rank order of lactating > cycling females > males, consistent with the reported secretory capacities of mammotropes from these sources. Interestingly, we observed that the basal level of PRL promotor-driven reporter activity was the same for all three models, but that mammotropes from males were the most responsive to stimulation of PRL gene expression by elevation of [Ca2+]i. Collectively, our findings reveal gender- and state-specific differences in Ca2+ dynamics and induction of PRL gene expression. These likely contribute to reported differences in secretory capacity.

Animals↗
PubMed2004

Reciprocal modulation of calcium dynamics at rod and cone photoreceptor synapses by nitric oxide.

The abundance of nitric oxide (NO) synthesizing enzymes identified in the vertebrate retina highlight the importance of NO as a signaling molecule in this tissue. Here we describe opposing actions of NO on the rod and cone photoreceptor synapse. Depolarization-induced increases of calcium concentration in rods and cones were enhanced and inhibited, respectively, by the NO donor S-nitrosocysteine. NO suppressed calcium current in cones by decreasing the maximum conductance, whereas NO facilitated rod Ca channel activation. NO also activated a nonselective voltage-independent conductance in both rods and cones. Suppression of NO production in the intact retina with N(G)-nitro-l-arginine favored cone over rod driven postsynaptic signals, as would be expected if NO enhanced rod and suppressed cone synaptic activity. These findings may imply involvement of NO in regulating the strength of rod and cone pathways in the retina during different states of adaptation.

Ambystoma↗
PubMed1998

Intracellular free calcium dynamics in stretch-injured astrocytes.

We have previously developed an in vitro model for traumatic brain injury that simulates a major component of in vivo trauma, that being tissue strain or stretch. We have validated our model by demonstrating that it produces many of the posttraumatic responses observed in vivo. Sustained elevation of the intracellular free calcium concentration ([Ca2+]i) has been hypothesized to be a primary biochemical mechanism inducing cell dysfunction after trauma. In the present report, we have examined this hypothesis in astrocytes using our in vitro injury model and fura-2 microphotometry. Our results indicate that astrocyte [Ca2+]i is rapidly elevated after stretch injury, the magnitude of which is proportional to the degree of injury. However, the injury-induced [Ca2+]i elevation is not sustained and returns to near-basal levels by 15 min postinjury and to basal levels between 3 and 24 h after injury. Although basal [Ca2+]i returns to normal after injury, we have identified persistent injury-induced alterations in calcium-mediated signal transduction pathways. We report here, for the first time, that traumatic stretch injury causes release of calcium from inositol trisphosphate-sensitive intracellular calcium stores and may uncouple the stores from participation in metabotropic glutamate receptor-mediated signal transduction events. We found that for a prolonged period after trauma astrocytes no longer respond to thapsigargin, glutamate, or the inositol trisphosphate-linked metabotropic glutamate receptor agonist trans-(1S,3R)-1-amino-1,3-cyclopentanedicarboxylic acid with an elevation in [Ca2+]i. We hypothesize that changes in calcium-mediated signaling pathways, rather than an absolute elevation in [Ca2+]i, is responsible for some of the pathological consequences of traumatic brain injury.

Animals↗
PubMed2006

Combined modulation of the mitochondrial ATP-dependent potassium channel and the permeability transition pore causes prolongation of the biphasic calcium dynamics.

The permeability transition pore (PTP) and the ATP-dependent potassium (mtK-ATP) channel of mitochondria are known to play key roles in mitochondrially mediated apoptosis. We investigated how modulation of the permeability transition pore (PTP) and the ATP-dependent potassium (mtK-ATP) channel, either as single elements or in combination, affects the proapoptotic intracellular calcium ([Ca(2+)](i)) transients and the mitochondrial membrane potential (psi(m)). For this purpose a model was established exploring the [Ca(2+)](i) transients in N2A cells using continuous application of ATP that causes a biphasic [Ca(2+)](i) response. This response was sensitive to endoplasmatic reticulum (ER) Ca(2+) depletion and a smooth ER Ca(2+)-ATPase (SERCA) antagonist. PTP inhibition by cyclosporine A (CsA) or its non-immunosuppressive derivative NIM811 caused an amplification of the secondary [Ca(2+)](i) peak and induced a hyperpolarization of psi(m). Both the putative mtK-ATP channel inhibitor 5-hydroxydecanoate (5-HD) and the opener diazoxide ameliorated the ATP-induced secondary [Ca(2+)](i) peak. The effect of diazoxide was accompanied by a depolarization of psi(m) whereas 5-HD had no effect on psi(m). When diazoxide and CsA or NIM811 were applied together the secondary [Ca(2+)](i) rise did not return to baseline and a not significant hyperpolarization of psi(m) was observed. So, simultaneous inhibition of PTP and activation of the mtK-ATP channel prevents the increased slope of the secondary [Ca(2+)](i) peak induced by CsA (or NIM811) and also the depolarization after diazoxide application. Hence, we propose that modulation of one of these channels leads to functional changes of the other channel by means of Delta[Ca(2+)](i) and Deltapsi(m).

Adenosine Triphosphate↗
PubMed2005

Calcium dynamics in dendritic spines, modeling and experiments.

Dendritic spines are microstructures, about one femtoliter in volume, where excitatory synapses are made with incoming afferents, in most neurons of the vertebrate brain. The spine contains all the molecular constituents of the postsynaptic side of the synapse, as well as a contractile element that can cause its movement in space. It also contains calcium handling machineries to allow fast buffering of excess calcium that influx through voltage and NMDA gated channels. The spine is connected to the dendrite through a thin neck that serves as a variable barrier between the spine head and the parent dendrite. We review a novel modeling approach that is more suitable for the accurate description of the stochastic behavior of individual molecules in microstructures. Using this approach, we predict the calcium handling ability of the spine in complex situations associated with synaptic activity, spine motility and plasticity.

Animals↗
PubMed1998

Calcium dynamics in single spines during coincident pre- and postsynaptic activity depend on relative timing of back-propagating action potentials and subthreshold excitatory postsynaptic potentials.

We compared the transient increase of Ca2+ in single spines on basal dendrites of rat neocortical layer 5 pyramidal neurons evoked by subthreshold excitatory postsynaptic potentials (EPSPs) and back-propagating action potentials (APs) by using calcium fluorescence imaging. AP-evoked Ca2+ transients were detected in both the spines and in the adjacent dendritic shaft, whereas Ca2+ transients evoked by single EPSPs were largely restricted to a single active spine head. Calcium transients elicited in the active spines by a single AP or EPSP, in spines up to 80 micro(m) for the soma, were of comparable amplitude. The Ca2+ transient in an active spine evoked by pairing an EPSP and a back-propagating AP separated by a time interval of 50 ms was larger if the AP followed the EPSP than if it preceded it. This difference reflected supra- and sublinear summation of Ca2+ transients, respectively. A comparable dependence of spinous Ca2+ transients on relative timing was observed also when short bursts of APs and EPSPs were paired. These results indicate that the amplitude of the spinous Ca2+ transients during coincident pre- and postsynaptic activity depended critically on the relative order of subthreshold EPSPs and back-propagating APs. Thus, in neocortical neurons the amplitude of spinous Ca2+ transients could encode small time differences between pre- and postsynaptic activity.

Action Potentials↗
PubMed2004

Confocal imaging of changes in glial calcium dynamics and homeostasis after mechanical injury in rat spinal cord white matter.

Periaxonal glia play an important role in maintaining axonal function in white matter. However, little is known about the changes that occur in glial cells in situ immediately after traumatic injury. We used fluo-3 and confocal microscopy to examine the effects of localized (<0.5 mm) mechanical trauma on intracellular calcium (Ca(i)(2+)) levels in glial cells in a mature rat spinal cord white matter preparation in vitro. At the injury site, the glial Ca(i)(2+) signal increased by 300-400% within 5 min and then irreversibly declined indicating cell lysis and death. In glial cells at sites adjacent to the injury (1.5-2 mm from epicenter), Ca(i)(2+) levels peaked at 10-15 min, and thereafter declined but remained significantly above rest levels. At distal sites (6-9 mm), Ca(i)(2+) levels rose and declined even slower, peaking at 80-90 min. Injury in zero calcium dampened Ca(i)(2+) responses, indicating a role for calcium influx in the generation and propagation of the injury-induced Ca(i)(2+) signal. By 50-80 min post-injury, surviving glial cells demonstrated an enhanced ability to withstand supraphysiological Ca(i)(2+) loads induced by the calcium ionophore A-23187. Glial fibrillary acidic protein (GFAP) and CNPase immunolabeling determined that the glial cells imaged with fluo-3 included both astrocytes and oligodendrocytes. These data provide the first direct evidence that the effects of localized mechanical trauma include a glial calcium signal that can spread along white matter tracts for up to 9 mm within less than 3 h. The results further show that trauma can enhance calcium regulation in surviving glial cells in the acute post-injury period.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1996

Imaging calcium dynamics in dendritic spines.

Recent advances in optical imaging technology have enabled the measurement of Ca2+ dynamics in individual synaptic spines with high time resolution. Results from work using this new technology have confirmed the view that individual synaptic spines can act as functional chemical compartments with independent dynamics of second-messenger concentration. In particular, the ability of Ca2+ to directly mediate Hebbian coincidence detection has been confirmed.

Animals↗
PubMed2002

Altered calcium dynamics do not account for attenuation of endothelium-derived hyperpolarizing factor-mediated dilations in the female middle cerebral artery.

BACKGROUND AND PURPOSE: The contribution of endothelium-derived hyperpolarizing factor (EDHF) to ATP-mediated dilations is significantly attenuated in the rat middle cerebral artery of intact and estrogen-treated ovariectomized (OVX) females compared with males and vehicle-treated OVX females. Since an increase in endothelial calcium appears to be a critical prerequisite in the EDHF response, we tested the hypothesis that endothelial cell intracellular calcium ([Ca(2+)](i)) fails to reach sufficient levels to elicit robust EDHF-mediated dilations in females and that this effect is mediated by estrogen. METHODS: Vascular diameter and [Ca(2+)](i) were measured concomitantly in perfused middle cerebral artery segments with the use of videomicroscopy and fura 2 fluorescence, respectively. RESULTS: In the presence of N(G)-nitro-L-arginine methyl ester and indomethacin, the dilation to 10(-5) mol/L ATP was significantly reduced (P<0.05) in intact females (42+/-8%; n=6) and estrogen-treated OVX females (25+/-6%; n=9) compared with intact males (89+/-5%; n=6) and vehicle-treated OVX females (92+/-2%; n=7). Contrary to our initial hypothesis, endothelial cell [Ca(2+)](i) increased to comparable levels in intact females (461+/-116 nmol/L), estrogen-treated OVX females (417+/-50 nmol/L), intact males (421+/-77 nmol/L), and vehicle-treated OVX females (530+/-92 nmol/L). In response to luminal ATP (10(-5) mol/L), smooth muscle cell [Ca(2+)](i) decreased to a greater degree in males (37+/-4%; n=8) compared with females (21+/-5%; n=7) and in vehicle-treated OVX females (18+/-7%; n=7) compared with estrogen-treated OVX females (3+/-5%; n=9). CONCLUSIONS: Our data suggest that loss of a factor coupling EDHF to reduction of ionized smooth muscle cell [Ca(2+)](i) accounts for the attenuated EDHF-mediated dilations in the female middle cerebral artery.

Animals↗
PubMed2005

Calcium dynamics in catecholamine-containing secretory vesicles.

We have used an aequorin chimera targeted to the membrane of the secretory granules to monitor the free [Ca(2+)] inside them in neurosecretory PC12 cells. More than 95% of the probe was located in a compartment with an homogeneous [Ca(2+)] around 40 microM. Cell stimulation with either ATP, caffeine or high-K(+) depolarization increased cytosolic [Ca(2+)] and decreased secretory granule [Ca(2+)] ([Ca(2+)](SG)). Inositol-(1,4,5)-trisphosphate, cyclic ADP ribose and nicotinic acid adenine dinucleotide phosphate were all ineffective to release Ca(2+) from the granules. Changes in cytosolic [Na(+)] (0-140 mM) or [Ca(2+)] (0-10 microM) did not modify either ([Ca(2+)](SG)). Instead, [Ca(2+)](SG) was highly sensitive to changes in the pH gradient between the cytosol and the granules. Both carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) and nigericin, as well as cytosolic acidification, reversibly decreased [Ca(2+)](SG), while cytosolic alcalinization reversibly increased [Ca(2+)](SG). These results are consistent with the operation of a H(+)/Ca(2+) antiporter in the vesicular membrane. This antiporter could also mediate the effects of ATP, caffeine and high-K(+) on [Ca(2+)](SG), because all of them induced a transient cytosolic acidification. The FCCP-induced decrease in [Ca(2+)](SG) was reversible in 10-15 min even in the absence of cytosolic Ca(2+) or ATP, suggesting that most of the calcium content of the vesicles is bound to a slowly exchanging Ca(2+) buffer. This large store buffers [Ca(2+)](SG) changes in the long-term but allows highly dynamic free [Ca(2+)](SG) changes to occur in seconds or minutes.

Aequorin↗
PubMed2005

Intracellular calcium dynamics and anisotropic reentry in isolated canine pulmonary veins and left atrium.

BACKGROUND: Rapid activations due to either focal discharge or reentry are often present during atrial fibrillation (AF) in the pulmonary veins (PVs). The mechanisms of these rapid activations are unclear. METHODS AND RESULTS: We studied 7 isolated, Langendorff-perfused canine left atrial (LA) and PV preparations and used 2 cameras to map membrane potential alone (Vm, n=3) or Vm and intracellular calcium simultaneously (Ca(i), n=4). Rapid atrial pacing induced 26 episodes of focal discharge from the proximal PVs in 5 dogs. The cycle lengths were 223+/-52 ms during ryanodine infusion (n=13) and 133+/-59 ms during ryanodine plus isoproterenol infusion (n=13). The rise of Ca(i) preceded Vm activation at the sites of focal discharge in 6 episodes of 2 preparations, compatible with voltage-independent spontaneous Ca(i) release. Phase singularities during pacing-induced reentry clustered specifically at the PV-LA junction. Periodic acid-Schiff (PAS) stain identified large cells with pale cytoplasm along the endocardium of PV muscle sleeves. There were abrupt changes in myocardial fiber orientation and increased interstitial fibrosis in the PV and at the PV-LA junction. CONCLUSIONS: PV muscle sleeves may develop voltage-independent Ca(i) release, resulting in focal discharge. Focal discharge may also be facilitated by the presence of PAS-positive cells that are compatible with node-like cells. During reentry, phase singularities clustered preferentially at sites of increased anisotropy such as the PV-LA junction. These findings suggest that focal discharge caused by spontaneous calcium release and anisotropic reentry both contribute to rapid activations in the PVs during AF.

Action Potentials↗
PubMed1999

Effects of antisense oligonucleotides to the cardiac Na+/Ca2+ exchanger on calcium dynamics in cultured cardiac myocytes.

The present study was designed to explore the role of the Na+/Ca2+ exchanger on spontaneous beating of cultured cardiac myocytes. Antisense oligonucleotides (AS) based on the sequence of the cardiac Na+/Ca2+ exchanger were used to decrease expression of this Ca2+ transporting protein in cardiac myocytes. An application of AS (10 microM) caused an increase in beating rate of myocytes within 6-24 h. After 24 h of exposure, AS increased the beating rate from an average rate of 77 beats/min in control and sense-treated myocytes to 103 beats/min. Moreover, myocytes treated for 24 h with 10 microM AS exhibited an increase in diastolic [Ca2+]i levels. The antisense treatment also led to a approximately 20% decrease in expression of Na+/Ca2+ exchanger proteins within 6-24 h. Changes in mRNA levels following AS treatment could not be detected within 3- to 24-h periods. The results of these studies suggest that the Na+/Ca2+ exchanger plays a potentiating role in spontaneous the beating process by regulating [Ca2+]i dynamics and that even a small reduction in the levels of the exchanger protein has marked effects on the handling of [Ca2+]i during the cardiac cycle.

Animals↗