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PubMedDate not supplied

Mechanism regulating nuclear calcium signaling.

Although the outer nuclear membrane is continuous with the endoplasmic reticulum, it is possible to isolate nuclei both intact and free from endoplasmic reticulum contaminants. The outer and the inner nuclear membranes can be purified free from cross-contamination. Evidence in support of autonomous regulation of nuclear calcium signaling relies upon the investigations with isolated nuclei. Mechanisms for generating calcium signaling in the nucleus have been identified. Two calcium transporting systems, an ATP-dependant nuclear Ca(2+)-ATPase and an IP4-mediated inositol 1,3,4,5-tetrakisphosphate receptor, are located on the outer nuclear membrane. Thus, ATP and IP4, depending on external free calcium concentrations, are responsible for filling the nuclear envelope calcium pool. The inositol 1,4,5-trisphosphate receptor is located on the inner nuclear membrane with its ligand binding domain facing toward the nucleoplasm. Likewise, the ryanodine receptor is located on the inner nuclear membrane and its ligand cADP-ribose is generated within the nucleus. A 120 kDa protein fragment of nuclear PLC-gamma1 is stimulated in vivo by epidermal growth factor nuclear signaling coincident with the time course of nuclear membrane epidermal growth factor receptor activation. Stimulated 120 kDa protein fragment interacts with PIKE, a nuclear GTPase, and together they form a complex with PI[3]kinase serving as a module for nuclear PI[3]K stimulation. Thus, the nucleus has its own IP(3) generating system.

Animals↗
PubMed2001

A new phospholipase-C-calcium signalling pathway mediated by cyclic AMP and a Rap GTPase.

Stimulation of phosphoinositide-hydrolysing phospholipase C (PLC) generating inositol-1,4,5-trisphosphate is a major calcium signalling pathway used by a wide variety of membrane receptors, activating distinct PLC-beta or PLC-gamma isoforms. Here we report a new PLC and calcium signalling pathway that is triggered by cyclic AMP (cAMP) and mediated by a small GTPase of the Rap family. Activation of the adenylyl cyclase-coupled beta2-adrenoceptor expressed in HEK-293 cells or the endogenous receptor for prostaglandin E1 in N1E-115 neuroblastoma cells induced calcium mobilization and PLC stimulation, seemingly caused by cAMP formation, but was independent of protein kinase A (PKA). We provide evidence that these receptor responses are mediated by a Rap GTPase, specifically Rap2B, activated by a guanine-nucleotide-exchange factor (Epac) regulated by cAMP, and involve the recently identified PLC-epsilon isoform.

Adenylyl Cyclases↗
PubMed2006

Calcium signalling and reactive oxygen species in non-excitable cells.

Reactive oxygen species can induce several biological processes by stimulating signal transduction components such as cytosolic free calcium concentration. The physiological significance of the role of biological oxidants in the regulation of calcium signalling pathway as well as the mechanisms of the oxidant-stimulation of signal transduction are discussed in this review.

Animals↗
PubMed1992

Time-varying and static magnetic fields act in combination to alter calcium signal transduction in the lymphocyte.

We have tested the hypothesis that extremely low frequency (ELF) time-varying magnetic fields act in combination with static magnetic fields to alter calcium signalling in the lymphocyte. Results indicate that a 60-min exposure of thymic lymphocytes at 37 +/- 0.05 degrees C to a 16 Hz, 421 mG (42.1 microT) magnetic field simultaneously with a colinear static magnetic field of 234 mG (23.4 microT) (a.c./d.c. field intensity ratio = 1.8) inhibits calcium influx triggered by the mitogen Concanavalin A. Significantly, resting lymphocytes do not respond to the fields, thus, only mitogen-activated cells undergoing calcium signalling exhibit a field response. These results indicate that signal transduction involving calcium is an important biological constraint which operates to mediate this field interaction. Additional split field exposures show that the presence of the a.c. field or the d.c. field alone does not produce an effect. This is consistent with a proposed parametric resonance theory of interaction of low intensity magnetic fields with biological systems (L.L. Lednev (1991) Bioelectromagnetics 12, 71-75), which predicts the occurrence of biological effects at specific values for the frequency and field intensity of the ELF and static magnetic fields.

Animals↗
PubMed2002

Activation of L-type calcium channels is required for gap junction-mediated intercellular calcium signaling in osteoblastic cells.

The propagation of mechanically induced intercellular calcium waves (ICW) among osteoblastic cells occurs both by activation of P2Y (purinergic) receptors by extracellular nucleotides, resulting in "fast" ICW, and by gap junctional communication in cells that express connexin43 (Cx43), resulting in "slow" ICW. Human osteoblastic cells transmit intercellular calcium signals by both of these mechanisms. In the current studies we have examined the mechanism of slow gap junction-dependent ICW in osteoblastic cells. In ROS rat osteoblastic cells, gap junction-dependent ICW were inhibited by removal of extracellular calcium, plasma membrane depolarization by high extracellular potassium, and the L-type voltage-operated calcium channel inhibitor, nifedipine. In contrast, all these treatments enhanced the spread of P2 receptor-mediated ICW in UMR rat osteoblastic cells. Using UMR cells transfected to express Cx43 (UMR/Cx43) we confirmed that nifedipine sensitivity of ICW required Cx43 expression. In human osteoblastic cells, gap junction-dependent ICW also required activation of L-type calcium channels and influx of extracellular calcium.

Animals↗
PubMed1998

Developmental changes in purinergic calcium signalling in rat neocortical neurones.

The changes in cytoplasm free calcium concentration ([Ca2+]i transients) were measured in Fura-2/AM loaded pyramidal neurones of sensorimotor cortex in acutely prepared slices isolated from 14 days (P14) and 30 (P30) days old rats. Ni2+ (50 microM) diminished the [Ca2+]i transients evoked by 50 mM KCl bath application by 47%+/-8% in neurones of the P14 group and only by 15%+/-6% in those of P30 group (P<0.002). Nifedipine and verapamil in concentration 100 microM reduced the calcium transients amplitude triggered by depolarization to about the same extent in both groups of neurons-on average by 50% and 35%, respectively. The amplitude of [Ca2+]i transients induced by application of 100 microM ATP reached 103+/-6 nM in P14 neurones and 72+/-8 nM in the P30 ones. The ATP-[Ca2+]i induced transient could be evoked in Ca2+-free external solution, indicating the presence of metabotropic (P2y) purinoreceptors. Almost all (90%) P14 neurones were endowed with such receptors. At the same time only 1/3 of the tested (n=42) P30 neurones presented responses to ATP applications in Ca2+-free solution. The share of ionotropic (P2x) purinoreceptors in generation of calcium signal was the same in both groups of neurons. No caffeine-induced Ca2+-release has been observed in the P14 neurons. To the contrary, in 28 cells from 42 investigated neurones of the P30 group application of 40 mM caffeine for 10 s induced considerable [Ca2+]i transients, which did not disappear in calcium-free solution. A conclusion is made about substantial changes in the expression of Ca2+-handling mechanisms which are occurring in neocortical neurones at the third-fourth week of postnatal development.

Aging↗
PubMed2006

Calcium signaling in lizard red blood cells.

The ion calcium is a ubiquitous second messenger, present in all eukaryotic cells. It modulates a vast number of cellular events, such as cell division and differentiation, fertilization, cell volume, decodification of external stimuli. To process this variety of information, the cells display a number of calcium pools, which are capable of mobilization for signaling purposes. Here we review the calcium signaling on lizards red blood cells, an interesting model that has been receiving an increasing notice recently. These cells possess a complex machinery to regulate calcium, and display calcium responses to extracellular agonists. Interestingly, the pattern of calcium handling and response are divergent in different lizard families, which enforces the morphological data to their phylogenetic classification, and suggest the radiation of different calcium signaling models in lizards evolution.

Animals↗
PubMed1998

Modulation of cell calcium signals by mitochondria.

It is now clearer and clearer that mitochondria play a role, and perhaps an active role, in cell calcium signalling. The fact that mitochondria can exhibit a Ca2+-induced Ca2+ release (mCICR, Ichas et al. [37]) reinforces this concept and makes the mitochondria an essential element in the relay of Ca2+ wave propagation. It must be emphasized that the modulation of cell Ca2+ signals by mitochondria depends upon their energetic status, thus making mitochondria an essential link between energy metabolism and calcium signalling inside the cell.

Adenine Nucleotides↗
PubMedDate not supplied

Calcium signaling in mitral cell dendrites of olfactory bulbs of neonatal rats and mice during olfactory nerve Stimulation and beta-adrenoceptor activation.

Synapses formed by the olfactory nerve (ON) provide the source of excitatory synaptic input onto mitral cells (MC) in the olfactory bulb. These synapses, which relay odor-specific inputs, are confined to the distally tufted single primary dendrites of MCs, the first stage of central olfactory processing. beta-adrenergic modulation of electrical and chemical signaling at these synapses may be involved in early odor preference learning. To investigate this possibility, we combined electrophysiological recordings with calcium imaging in olfactory bulb slices prepared from neonatal rats and mice. Activation of ON-MC synapses induced postsynaptic potentials, which were associated with large postsynaptic calcium transients. Neither electrical nor calcium responses were affected by beta-adrenergic agonists or antagonist. Immunocytochemical analysis of MCs and their tufted dendrites revealed clear immunoreactivity with antibodies against alpha1A (Cav2.1, P/Q-type) and alpha1B (Cav2.2, N-type), but not against alpha1C (Cav1.2, L-type) or alpha1D (Cav1.3, L-type) calcium channel subunits. Moreover, nimodipine, a blocker of L-type calcium channels, had no effect on either electrical or calcium signaling at ON-MC synapses. In contrast to previous evidence, we concluded that in neonatal rats and mice (P5-P8), mitral cells do not express significant amounts of L-type calcium channels, the calcium channel type that is often targeted by beta-adrenergic modulation. The absence of beta-adrenergic modulation on either electrical or calcium signaling at ON-MC synapses of neonatal rats and mice excludes the involvement of this mechanism in early odor preference learning.

Afferent Pathways↗
PubMed2006

Mechanisms of calcium signaling and function in lymphocytes.

The multifunctional role for calcium during lymphocyte activation and differentiation is well established; yet how fate-specific changes in calcium concentration are produced, and how these signals are translated into distinct cellular responses, is not known. A critical role has been identified for store-operated calcium release-activated calcium (CRAC) channels; however, the lack of information concerning the structure and mechanism of store-dependent activation has limited our ability to define CRAC's role in the range of calcium-dependent responses of lymphocytes. Moreover, additional calcium-permeant cation channels have been recently identified in lymphocytes. These channels regulate functions distinct from those attributed to CRAC channels. Consequently, this review summarizes well-established mechanisms of calcium signaling and also considers recent findings which suggest that diverse and interacting pathways encode functionally specific calcium signals in lymphocytes. Speculation is also offered about how distinct patterns of calcium signaling are translated into diverse transcriptional responses.

Animals↗
PubMed2001

Weak TCR stimulation induces a calcium signal that triggers IL-4 synthesis, stronger TCR stimulation induces MAP kinases that control IFN-gamma production.

Th1 and Th2 cells produce different cytokines and have distinct functions. Th1/Th2 cell differentiation is influenced, among other factors, by the nature of TCR-MHC interactions. However, how the TCR transduces a signal resulting in IFN-gamma or IL-4 production is a matter of debate. For example, some authors reported a loss of calcium signaling pathway in Th2 cells. We used a T cell hybridoma producing IL-4 upon weak TCR stimulation and both IL-4 and IFN-gamma for strong TCR engagement as a model to study how TCR signaling pathways are differentially activated in both conditions of stimulation and how this influences the production of cytokines. We show that: (1) the calcium response is identical following weak and strong TCR stimulation; (2) mitogen-activated protein kinase(MAPK) activation is a gradual phenomenon depending upon the strength of TCR activation; (3) a calcium response, even weak, triggers IL-4 expression; (4) IFN-gamma synthesis requires not only a calcium response but also MAPK activation. The MAPK pathway is dispensable for IL-4 production, although it amplifies IL-4 synthesis upon strong TCR stimulation; (5) TCR-induced IL-4 production also depends on calcium signaling in Th2 cells, while IFN-gamma synthesis is dependent, in addition, on MAPK activation in Th1 cells.

Animals↗
PubMed2001

Cell-cell adhesion in human fibroblasts requires calcium signaling.

In connective tissues, intercellular adhesion is essential for tissue morphogenesis, development and wound healing. However, the signaling mechanisms initiated by cell-cell adhesion in fibroblasts and that regulate it are not known. In this study we tested the hypothesis that intracellular calcium signaling is required to mediate intercellular adhesion between fibroblasts. Fura-2 or fluo-3 labeled human fibroblasts were used to investigate calcium homeostasis during intercellular adhesion. After contact with suspended fibroblasts there was a rise in cytosolic free calcium ([Ca2+]i) and multiple calcium oscillations in substrate-attached cells. Antibodies against the extracellular but not the cytoplasmic domain of cadherin induced a similar calcium response, indicating that these responses were initiated by cadherin binding. As shown by the near-plasma membrane Ca2+ indicator (Fura-C18) and by confocal microscopy of fluo-3-loaded cells, [Ca2+]i transients probably originated at sites of cell-cell contact. Cell-cell adhesion was dependent on both calcium influx through membrane channels and release of Ca2+ from internal calcium stores, because the calcium channel inhibitor LaCl3 or pretreatment of cells with thapsigargin significantly inhibited (>35%) cell-cell attachment. The [Ca2+]i changes induced by cell-cell adhesion were temporally correlated with increased recruitment of intercellular junctional proteins into the cytoskeleton and movement of GFP-actin to sites of cell-cell contact. [Ca2+]i responses induced by intercellular adhesion were essential for both junctional protein recruitment and the establishment of strong cell-cell contacts, as loading cells with BAPTA/AM significantly inhibited cell-cell adhesion and recruitment of cadherins and beta-catenin to the actin cytoskeleton. Actin depolymerization by cytochalasin D dramatically reduced cell-cell adhesion and recruitment of cadherins and catenin to the actin cytoskeleton. These results demonstrate that cadherin-cadherin interaction induces [Ca2+]i transients during cell-cell adhesion in fibroblasts, and these calcium signals regulate cell-cell adhesion through remodeling of cortical actin and recruitment of cadherins and beta-catenin into intercellular junctions.

Actin Cytoskeleton↗
PubMed1991

Antigen receptor-mediated calcium signals in B cells as revealed by confocal fluorescence microscopy.

A confocal fluorescence microscope was used to study the antigen receptor-mediated calcium signals in B cells. Anti-IgD binding to B lymphoma cells (BAL17) increased the intracellular calcium concentration with short lag times. Confocal fluorescence images of the fluo-3-loaded BAL17 cells showed that the intracellular calcium ion concentrations increased non-homogeneously, suggesting that the calcium signals transferred not only to the cytoplasm but also to the nucleus.

Antibodies↗
PubMed1997

Calcium signaling mechanisms in renal vascular responses to vasopressin in genetic hypertension.

Previous blood flow studies demonstrated that arginine vasopressin (AVP) produces exaggerated renal vasoconstriction in young spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto control rats (WKY). The purpose of the present study was to determine the role of postreceptor calcium signaling pathways in AVP-induced renal vasoconstriction in vivo. Renal blood flow (RBF) was measured by electromagnetic flowmetry in anesthetized, water-loaded, 8-week-old WKY and SHR pretreated with indomethacin to avoid interactions with prostaglandins. AVP was injected into the renal artery to produce a transient 25% to 30% decrease in RBF without affecting arterial pressure. To achieve similar control levels of vasoconstriction, SHR received a lower dose (2 versus 5 ng). Coadministration of nifedipine with AVP produced dose-dependent inhibition of the AVP-induced renal vasoconstriction. Nifedipine exerted maximum inhibition by blocking 30% to 35% of the peak AVP response, indicating the involvement of dihydropyridine-sensitive voltage-dependent calcium channels. To evaluate intracellular calcium mobilization, 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) or heparin was coadministered with AVP. Each agent produced a dose-dependent inhibition of up to 65% of the maximum blood flow change produced by AVP. The degrees of inhibition produced by maximum effective doses of nifedipine and TMB-8 were additive; the combination blocked up to 85% of the response to AVP. These observations indicate that about one third of the AVP-induced constriction of renal resistance vessels is mediated by voltage-dependent L-type calcium channels responsive to the dihydropyridine nifedipine. Approximately two thirds of the change in vascular tone is due to inositol 1,4,5-trisphosphate-mediated calcium mobilization from intracellular sources sensitive to TMB-8 and heparin. The results suggest that the exaggerated renal vascular reactivity to AVP challenge in SHR is probably not due to a strain difference in postreceptor calcium signal transduction. After AVP receptor stimulation, calcium mobilization and calcium entry signaling pathways participate to similar degrees in WKY and SHR.

Animals↗
PubMed2006

Passive sensitization increases histamine-stimulated calcium signaling and NF-kappaB transcription activity in bronchial epithelial cells.

AIM: To find out if the two aspects of asthma (chronic airway inflammation and bronchial hyperresponsiveness) are related to hypersensitivity of calcium signaling in bronchial epithelial cells. METHODS: Porcine bronchial epithelial cells (PBEC) were divided into sensitized (S) and non-sensitized (N) groups. In group S, the cells were preincubated with serum from ovalbumin sensitized guinea pigs. In group N, the cells were preincubated with serum from nonsensitized guinea pigs. Single cell calcium imaging and ELISA-based NF-kappaB activity were used to evaluate the histamine-stimulated intracellular free calcium level and NF-kappaB activity, respectively. RESULTS: First, 0.1 micromol/L histamine could induce [Ca(2+)](i) oscillations in PBEC of group S, but not in group N. Second, 1 micromol/L histamine could induce [Ca(2+)](i) oscillations of PBEC in both group S and group N. The [Ca(2+)](i) oscillation frequency of PBEC was significantly higher in group S than in group N, though the [Ca(2+)](i) oscillation amplitude showed no difference between the two groups. Finally, when 10 micromol/L histamine was used to stimulate PBEC, a transient initial increase followed by a sustained elevation (FSE) of [Ca(2+)](i) was observed in PBEC in both groups. The amplitude of the FSE of [Ca(2+)](i) in PBEC was significantly higher in group S than in group N. The subsequent NF-kappaB activity was in accordance to the calcium oscillation frequency evoked by histamine, but not to the amplitude. CONCLUSION: It was suggested that the increased sensitivity of calcium signaling in bronchial epithelial cells might contribute to the exorbitant inflammation or increased susceptibility in asthmatic airway epithelial cells.

Animals↗
PubMed1995

Serotonin-induced calcium signaling via 5-HT1A receptors in human leukemia (K 562) cells.

In this study, serotonin (5-HT) was found to diminish the intracellular calcium, [Ca2+]i, concentrations in a dose-dependent manner in Fura-2-loaded human leukemia (K 562) cells. Prior addition of verapamil (a calcium channel blocker) to the cells abolished the serotonin-induced response, suggesting that the diminution of free [Ca2+]i contents was due to the opening of calcium channels. Thapsigargin (an agent which increases [Ca2+]i via its action on endoplasmic reticulum) augmented the [Ca2+]i contents. Addition of serotonin before or after thapsigargin (THAP) curtailed the THAP-stimulated increases in [Ca2+]i, supporting the notion that 5-HT acts on the calcium channels and that it empties, in part, the THAP-stimulated calcium contents. Spiperone and NAN-190, antagonists to 5-HT1A receptor subtype, abolished the serotonin effects on calcium signaling, whereas an agonist to 5-HT1A receptor, 8OHDPAT, mimicked the serotonin-like action on the diminution of the intracellular calcium contents. These results indicate that the 5-HT response is mediated via 5-HT1A serotonergic receptors in these cells. Furthermore, we characterized the 5-HT receptors in K 562 cells. The specific binding of serotonin to these cells was saturable and hyperbolic. The Kd and the Bmax of serotonin binding were 100 nM and 1690 fmol/10(6) cells, respectively. 8-[3H]OH-DPAT also labeled these cells with a Bmax of 2.8 fmol/10(6) cells and a Kd of 20 nM. The specific binding of 8-[3H]OH-DPAT to K 562 cells was displaced by serotonin, 8OH-DPAT, and NAN-190. These results suggest that K 562 cells possess functional 5-HT1A receptors coupled with calcium signaling.

8-Hydroxy-2-(di-n-propylamino)tetralin↗