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PubMed1993

Calcium signaling in the brain.

Calcium ions regulate many processes in the central nervous system via interaction with intracellular calcium-binding proteins. One class of these proteins shares a common structural motif, the EF-hand. A consensus amino acid sequence for this motif has aided the identification of many new members of this family. Some of these proteins, like parvalbumin, calbindin, and calretinin, proved to be useful neuronal markers for a variety of functional brain systems and their circuitries. Their major role is assumed to be buffering, transport of Ca2+, and regulation of various enzyme systems. Cellular degeneration is often accompanied by Ca2+ overload. It has been assumed that neurons containing certain intracellular Ca(2+)-binding proteins may have a greater capacity to buffer Ca2+ and therefore would be more resistant to degeneration.

Animals↗
PubMed1999

Listeria monocytogenes phospholipase C-dependent calcium signaling modulates bacterial entry into J774 macrophage-like cells.

Listeria monocytogenes secretes several proteins that have been shown to contribute to virulence. Among these is listeriolysin O (LLO), a pore-forming hemolysin that is absolutely required for virulence. Two other virulence factors are phospholipases: a phosphatidylinositol-specific phospholipase C (PI-PLC [plcA]) and a broad-range PLC (plcB). Although mutations in plcA or plcB resulted in small increases in mouse 50% lethal dose (LD50), deletions in both genes resulted in a 500-fold increase in LD50. We have examined the role of these secreted proteins in host intracellular signaling in the J774 macrophage-like cell line. Measurements of cytosolic free calcium ([Ca2+]i) have revealed a rapid spike upon exposure of these cells to wild-type L. monocytogenes. This is followed by a second peak at 5 min and a third prolonged peak with a maximal [Ca2+]i of 800 to 1,000 nM. The pattern of calcium changes was greatly altered by deletion of any of the three virulence factors. An LLO mutant produced none of these elevations in [Ca2+]i; however, a transient elevation was observed whenever these bacteria entered the cell. A PI-PLC mutant produced a diminished single elevation in [Ca2+]i at 15 to 30 min. A broad-range PLC mutant produced only the first calcium spike. Studies with inhibitors suggested that the first elevation arises from influx of calcium from the extracellular medium through plasma membrane channels and that the second and third elevations come from release of Ca2+ from intracellular stores. We observed that internalization of wild-type bacteria and the broad-range PLC mutant was delayed for 5 to 10 min, but the LLO and PI-PLC mutants were internalized rapidly upon infection. Inhibitors that affected calcium signaling changed the kinetics of association of wild-type bacteria with J774 cells, the kinetics of entry, and the efficiency of escape from the primary phagosome.

Bacterial Proteins↗
PubMed2004

Various nondigestible saccharides open a paracellular calcium transport pathway with the induction of intracellular calcium signaling in human intestinal Caco-2 cells.

Ingestion of soluble nondigestible saccharides increases calcium absorption, and it is suggested that paracellular calcium transport contributes to this effect. However, cellular mechanisms and the contribution of active transport have not been clarified. This study examined the effects of 4 nondigestible saccharides, difructose anhydride (DFA) III, DFAIV, fructooligosaccharides, and raffinose, on active and passive calcium transport, permeability of paracellular pathways, and intracellular calcium signaling in a human intestinal Caco-2 cell monolayer. Net, active, and passive calcium transport were evaluated using (45)Ca. Transepithelial electrical resistance (TEER) and transport of lucifer yellow were measured as indicators of paracellular passage in differentiated Caco-2 cell monolayers incubated with 0-100 mmol/L of the various saccharides. The changes in intracellular calcium ion concentrations ([Ca(2+)](i)) were measured by fura-2 loading before and after the addition of each saccharide (50 or 100 mmol/L). The addition of 100 mmol/L of each saccharide to the apical medium of the Caco-2 cells enhanced net calcium transport without any changes in active calcium transport. Relative TEER was dose dependently and reversibly decreased by the addition of saccharides, and the decreases in TEER were highly correlated with net calcium transport (P < 0.001). Basolateral application of the saccharides had a slight or no effect on indicators of the paracellular pathway. Each saccharide caused an immediate and dose-dependent rise in [Ca(2+)](i) in the cells. The 4 nondigestible saccharides increased net calcium transport in the cells via the paracellular route through tight junctions. The rise in [Ca(2+)](i) induced by these saccharides may be involved in the opening of tight junctions.

Biological Transport↗
PubMed1998

An anaphase calcium signal controls chromosome disjunction in early sea urchin embryos.

A transient increase in intracellular calcium concentration [Ca2+]i occurs throughout the cell as sea urchin embryos enter anaphase of the first cell cycle. The transient just precedes chromatid disjunction and spindle elongation. Microinjection of calcium chelators or heparin, an InsP3 receptor antagonist, blocks chromosome separation. Photorelease of calcium or InsP3 can reverse the block. Nuclear reformation is merely delayed by calcium antagonists at concentrations that block chromatid separation. Thus, the calcium signal triggers the separation of chromatids, while calcium-independent pathways can bring about the alterations in microtubule dynamics and nuclear events associated with anaphase progression. That calcium triggers chromosome disjunction alone is unexpected. It helps explain previous conflicting results and allows the prediction that calcium plays a similar role at anaphase in other cell types.

Anaphase↗
PubMed2004

Possible link of different slow calcium signals generated by membrane potential and hormones to differential gene expression in cultured muscle cells.

The study of fluorescent calcium signals from cultured rat myotubes has provided interesting results in the past few years. Both K+ depolarization and tetanic electrical stimulation were shown to produce slow Ca2+ signals, unrelated to contraction and associated to regulation of gene expression in cultured rat myotubes. We studied the effect of IGF-I, insulin and testosterone on intracellular Ca2+ in cultured muscle cells. Insulin produced a fast (< 1 s) and transient [Ca2+] increase lasting less than 10 s. IGF-I induced a transient [Ca2+] increase, reaching a fluorescence peak 6 s after stimulus, to return to basal values after 60 s. Testosterone induced delayed (35 s) and long lasting (100-200 s) signals, frequently associated with oscillations. IGF-I, testosterone and electrical stimulation-induced Ca2+ signals were shown to be dependent on IP3 production. All of these Ca2+ signals were blocked by inhibitors of the IP3 pathway. On the other hand, insulin-induced Ca2+ increase was dependent on ryanodine receptors and blocked by either nifedipine or ryanodine. The different intracellular Ca2+ patterns produced by electrical stimulation, testosterone, IGF-I and insulin, may help to understand the role of intracellular calcium kinetics in the regulation of gene expression by various stimuli in skeletal muscle cells.

Animals↗
PubMed2006

Calcium signaling networks channel plant K+ uptake.

Potassium channel function is fundamental to many physiological processes in plants. In this issue of Cell, identify a protein complex in Arabidopsis consisting of a potassium channel, a protein kinase, and a calcium sensor. This study reveals that plants cope with limited soil potassium by coupling potassium channel activation to a cellular calcium signaling network.

Arabidopsis↗
PubMed2003

Absence of Whisker-related pattern formation in mice with NMDA receptors lacking coincidence detection properties and calcium signaling.

Precise refinement of synaptic connectivity is the result of activity-dependent mechanisms in which coincidence-dependent calcium signaling by NMDA receptors (NMDARs) under control of the voltage-dependent Mg2+ block might play a special role. In the developing rodent trigeminal system, the pattern of synaptic connections between whisker-specific inputs and their target cells in the brainstem is refined to form functionally and morphologically distinct units (barrelettes). To test the role of NMDA receptor signaling in this process, we introduced the N598R mutation into the native NR1 gene. This leads to the expression of functional NMDARs that are Mg2+ insensitive and Ca2+ impermeable. Newborn mice expressing exclusively NR1 N598R-containing NMDARs do not show any whisker-related patterning in the brainstem, whereas the topographic projection of trigeminal afferents and gross brain morphology appear normal. Furthermore, the NR1 N598R mutation does not affect expression levels of NMDAR subunits and other important neurotransmitter receptors. Our results show that coincidence detection by, and/or Ca2+ permeability of, NMDARs is necessary for the development of somatotopic maps in the brainstem and suggest that highly specific signaling underlies synaptic refinement.

Alleles↗
PubMed2004

Regulation of calcium signalling by 1-O-alkylglycerols in human Jurkat T lymphocytes.

We studied the role of natural occurring 1-O-alkylglycerols on the calcium signalling in Jurkat T-cells. Alkylglycerols evoked an increase in free intracellular calcium concentration [Ca2+]i, in a dose-dependent manner. When the experiments were performed in calcium-free buffer, the alkylglycerol response on the rise of [Ca2+]i was wholly abolished compared with the one in calcium-containing buffer, suggesting that these etherlipids induce a calcium influx by the opening of Ca2+ channels. We further employed inhibitors of voltage-gated calcium channels. We observed that omega-conotoxin, a blocker of N-type voltage-activated Ca2+ channels, but not verapamil, a blocker of L-type voltage-activated Ca2+ channels, curtailed significantly the calcium rise evoked by the lipid agents. Alkylglycerols also induced plasma membrane depolarisation, known to be involved in the opening of the voltage-gated calcium channels. Our study shows that alkylglycerols increase [Ca2+]i influx in human Jurkat T-cells possibly by modulating the permeability of calcium channels.

Animals↗
PubMed2004

Calcium signaling in isolated skeletal muscle fibers investigated under "Silicone Voltage-Clamp" conditions.

In skeletal muscle, release of calcium from the sarcoplasmic reticulum (SR) represents the major source of cytoplasmic Ca2+ elevation. SR calcium release is under the strict command of the membrane potential, which drives the interaction between the voltage sensors in the t-tubule membrane and the calcium-release channels. Either detection or control of the membrane voltage is thus essential when studying intracellular calcium signaling in an intact muscle fiber preparation. The silicone-clamp technique used in combination with intracellular calcium measurements represents an efficient tool for such studies. This article reviews some properties of the plasma membrane and intracellular signals measured with this methodology in mouse skeletal muscle fibers. Focus is given to the potency of this approach to investigate both fundamental aspects of excitation-contraction coupling and potential alterations of intracellular calcium handling in some muscle diseases.

Animals↗
PubMedDate not supplied

Intracellular calcium signals and control of cell proliferation: how many mechanisms?

The progression through the cell cycle in non-transformed cells is under the strict control of extracellular signals called mitogens, that act by eliciting complex cascades of intracellular messengers. Among them, increases in cytosolic free calcium concentration have been long realized to play a crucial role; however, the mechanisms coupling membrane receptor activation to calcium signals are still only partially understood, as are the pathways of calcium entry in the cytosol. This article centers on the role of calcium influx from the extracellular medium in the control of proliferative processes, and reviews the current understanding of the pathways responsible for this influx and of the second messengers involved in their activation.

Animals↗
PubMedDate not supplied

Calcium signaling and synaptic modulation: regulation of endocannabinoid-mediated synaptic modulation by calcium.

Postsynaptic Ca2+ signal influences synaptic transmission through multiple mechanisms. Some of them involve retrograde messengers that are released from postsynaptic neurons in a Ca2+-dependent manner and modulate transmitter release through activation of presynaptic receptors. Recent studies have revealed essential roles of endocannabinoids in retrograde modulation of synaptic transmission. Endocannabinoid release is induced by either postsynaptic Ca2+ elevation alone or activation of postsynaptic Gq/11-coupled receptors with or without Ca2+ elevation. The former pathway is independent of phospholipase Cbeta (PLCbeta) and requires a large Ca2+ elevation to a micromolar range. The latter pathway requires PLCbeta and is facilitated by a moderate Ca2+ elevation to a submicromolar range. This facilitation is caused by Ca2+-dependency of receptor-driven PLCbeta activation. The released endocannabinoids then activate presynaptic cannabinoid receptor type 1 (CB1), and suppress transmitter release from presynaptic terminals. Both CB1 receptors and Gq/11-coupled receptors are widely distributed in the brain. Thus, the endocannabinoid-mediated retrograde modulation may be an important and widespread mechanism in the brain, by which postsynaptic events including Gq/11-coupled receptor activation and Ca2+ elevation can retrogradely influence presynaptic function.

Animals↗
PubMed2005

Calcium signaling in cardiac ventricular myocytes.

Calcium (Ca) is a multifunctional regulator of diverse cellular functions. In cardiac muscle Ca is a direct central mediator of electrical activation, ion channel gating, and excitation-contraction (E-C) coupling that all occur on the millisecond time scale. The key amplification step in E-C coupling is under tight control of very local [Ca]. Ca also directly activates signaling via kinases and phosphatases (e.g., Ca-calmodulin-dependent protein kinase [CaMKII] and calcineurin) that occur over a longer time scale (seconds to minutes), and the co-localization of these Ca-dependent modulators to their targets and to Ca is also critical in distinct signaling pathways. Finally, Ca-dependent signaling is also involved in long-term (minutes to hours/days) alterations in gene expression (or excitation-transcription coupling). These pathways are involved in hypertrophy and heart failure, and they can alter the expression of some of the key Ca regulatory proteins involved in E-C coupling and their regulation by kinases and phosphatases. There may again be physical microenvironments involved in this nuclear transcription, such that they sense a discrete Ca signal that is distinct from that involved in E-C coupling. In this way cells can use Ca signaling in multiple ways that function in spatially and temporally distinct manners.

Animals↗
PubMed2003

Role of nucleotide P2 receptors in calcium signaling and prolactin release in pituitary lactotrophs.

Anterior pituitary cells express nucleotide-gated G protein-coupled P2 receptors (P2YRs) and cation-conducting channels (P2XRs). However, the identification of P2 receptors subtypes and their native ligands, and the distribution and function of these receptors within the secretory and non-secretory pituitary cells has been incompletely characterized. The focus in this study was on lactotroph subpopulation of cells. ATP and ADP, but not UTP and UDP, triggered calcium signaling in a majority (85%) of lactotrophs and prolactin release in mixed pituitary cells. Consistent with the role of P2 receptors in signaling and secretion, the actions of ATP and ADP were abolished in the presence of apyrase, an ectonucleotidase. Transcripts for Gq-coupled calcium-mobilizing P2Y1R, P2Y2R, P2Y4R, and P2Y6R, as well as Gi-coupled P2Y12R, were identified in mixed anterior pituitary cells. The ligand-selectivity profile of calcium mobilization-dependent signaling and prolactin secretion and the blockade of these responses by pyridoxal 5-phosphate 6-azophenyl-2',4'-disulphonic acid indicated that P2Y1R mediates the stimulatory action of ATP and ADP. Within the channels expressed in anterior pituitary (P2X2R, P2X3R, P2X4R, and P2X7R), the P2X4R subtype provides a major pathway for calcium influx-dependent signaling and prolactin secretion. This conclusion was based on comparison of native to recombinant channels with respect to their ligand preference, sensitivity to pyridoxal 5-phosphate 6-azophenyl-2',4'-disulphonic acid, and the rates of calcium signal desensitization.

Adenosine Diphosphate↗
PubMed1983

Duration of the calcium signal in the mitogenic stimulation of thymocytes.

An increase in the free cytoplasmic Ca2+ concentration in thymocytes can be detected by the fluorescent indicator quin 2 within a few seconds of the addition of concanavalin A and the response is quantified from the increased proportion of quin 2 in the cells chelated by Ca2+ ('% Ca-quin 2'). The % Ca-quin 2 in untreated cells is 53 +/- 6%, increases to 64 +/- 7% immediately after the addition of concanavalin A and declines spontaneously over 24 h back to the level in untreated cells (53 +/- 6%). The increase in % Ca-quin 2 in response to concanavalin A is completely blocked when 50 mM-alpha-methyl D-mannoside is added before concanavalin A and completely reversed when the competing sugar is added immediately after the mitogen. Addition of alpha-methyl D-mannoside at increasing intervals after concanavalin A addition causes a progressively smaller decrease in % Ca-quin 2 and has a negligible effect after 24 h, when the % Ca-quin 2 is the same as that in untreated cells. The decline in the calcium signal defined by these experiments has a similar time course to cap formation by concanavalin A on the cells. It is concluded that the calcium signal lasts only while concanavalin A is bound to the cell surface and is terminated either by capping or by the addition of alpha-methyl D-mannoside.

Aminoquinolines↗
PubMed2002

Effect of hyperglycemia on the basal cytosolic free calcium level, calcium signal and tyrosine-phosphorylation in human T-cells.

In this study, we investigated the effect of in vitro hyperglycemia on the function of human T-cells (Jurkat cells). Hyperglycemic conditions caused concentration-dependent elevation of basal cytosolic free calcium level and reduced calcium signal (activation capacity), either after ionomycin or monoclonal anti-CD3 antibody treatments. Similar changes were observed if cells were treated with the calcineurin inhibitor Cyclosporin-A. We found that tyrosine-phosphorylation after anti-CD3 treatment was also impaired. High glucose concentrations in the tissue culture medium are also associated with increased non-enzymatic glycation of T-cell proteins. We propose that the increased glycation of proteins involved in calcium transport and/or intracellular signal transduction in T-cells accounts for the abnormal calcium sequestration and calcium mediated signal transduction.

Antibodies, Monoclonal↗
PubMed1999

Calcium signaling and cytotoxicity.

The divalent calcium cation Ca(2+) is used as a major signaling molecule during cell signal transduction to regulate energy output, cellular metabolism, and phenotype. The basis to the signaling role of Ca(2+) is an intricate network of cellular channels and transporters that allow a low resting concentration of Ca(2+) in the cytosol of the cell ([Ca(2+)]i) but that are also coupled to major dynamic and rapidly exchanging stores. This enables extracellular signals from hormones and growth factors to be transduced as [Ca(2+)]i spikes that are amplitude and frequency encoded. There is considerable evidence that a number of toxic environmental chemicals target these Ca(2+) signaling processes, alter them, and induce cell death by apoptosis. Two major pathways for apoptosis will be considered. The first one involves Ca(2+)-mediated expression of ligands that bind to and activate death receptors such as CD95 (Fas, APO-1). In the second pathway, Ca(2+) has a direct toxic effect and its primary targets include the mitochondria and the endoplasmic reticulum (ER). Mitochondria may respond to an apoptotic Ca(2+) signal by the selective release of cytochrome c or through enhanced production of reactive oxygen species and opening of an inner mitochondrial membrane pore. Toxic agents such as the environmental pollutant tributyltin or the natural plant product thapsigargin, which deplete the ER Ca(2+) stores, will induce as a direct result of this effect the opening of plasma membrane Ca(2+) channels and an ER stress response. In contrast, under some conditions, Ca(2+) signals may be cytoprotective and antagonize the apoptotic machinery.

Animals↗
PubMed2004

Sphingosine-1-phosphate mediates calcium signaling in guinea pig enteroglial cells.

The enteric nervous system, which regulates multiple aspects of digestive activity, is composed of two major cell types, neurons and glial cells. Enteric glia, but not enteric neurons, respond to bioactive lipids with calcium signaling. The sphingomyelin metabolite sphingosine-1-phosphate (S1P) caused dose-dependent calcium (Ca(2+)) signaling using extracellular and intracellular Ca(2+). The signal transduction cascade was pertussis toxin-insensitive and involved an extracellular receptor since repetitive exposure yielded diminished responsiveness. Inhibition of either phospholipase C or the inositol 1,4,5-trisphosphate receptor abolished S1P effects. RT-PCR analysis demonstrated the presence of S1P-coupled endothelial differentiation gene (EDG) receptor mRNAs (EDG-1, EDG-3, and EDG-5) within the enteric nervous system. Immunocytochemical analysis demonstrated strong expression of both EDG-1 and EDG-3 and weak expression of EDG-5 in enteric glial cells. Other sphingomyelin cycle components, including sphingomyelin, sphingomyelinase, and sphingosine caused Ca(2+) transients in enteric glia. Related lipids lysophosphatidic acid and sphingosylphosphorylcholine also induced Ca(2+) signaling in enteric glia, suggesting that multiple lipid-activated signaling mechanisms exist in these cells.

Animals↗
PubMed2006

The roles of calcium signaling and ERK1/2 phosphorylation in a Pax6+/- mouse model of epithelial wound-healing delay.

BACKGROUND: Congenital aniridia caused by heterozygousity at the PAX6 locus is associated with ocular surface disease including keratopathy. It is not clear whether the keratopathy is a direct result of reduced PAX6 gene dosage in the cornea itself, or due to recurrent corneal trauma secondary to defects such as dry eye caused by loss of PAX6 in other tissues. We investigated the hypothesis that reducing Pax6 gene dosage leads to corneal wound-healing defects. and assayed the immediate molecular responses to wounding in wild-type and mutant corneal epithelial cells. RESULTS: Pax6+/- mouse corneal epithelia exhibited a 2-hour delay in their response to wounding, but subsequently the cells migrated normally to repair the wound. Both Pax6+/+ and Pax6+/- epithelia activated immediate wound-induced waves of intracellular calcium signaling. However, the intensity and speed of propagation of the calcium wave, mediated by release from intracellular stores, was reduced in Pax6+/- cells. Initiation and propagation of the calcium wave could be largely decoupled, and both phases of the calcium wave responses were required for wound healing. Wounded cells phosphorylated the extracellular signal-related kinases 1/2 (phospho-ERK1/2). ERK1/2 activation was shown to be required for rapid initiation of wound healing, but had only a minor effect on the rate of cell migration in a healing epithelial sheet. Addition of exogenous epidermal growth factor (EGF) to wounded Pax6+/- cells restored the calcium wave, increased ERK1/2 activation and restored the immediate healing response to wild-type levels. CONCLUSION: The study links Pax6 deficiency to a previously overlooked wound-healing delay. It demonstrates that defective calcium signaling in Pax6+/- cells underlies this delay, and shows that it can be pharmacologically corrected. ERK1/2 phosphorylation is required for the rapid initiation of wound healing. A model is presented whereby minor abrasions, which are quickly healed in normal corneas, transiently persist in aniridic patients, compromising the corneal stroma.

Animals↗