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At least 1,225 records · Page 68Linked to original sources
PubMed1997

Mitochondria are excitable organelles capable of generating and conveying electrical and calcium signals.

We report Ca2(+)-induced release of Ca2+ from mitochondria (mCICR) dependent on transitory opening of the permeability transition pore (PTP) operating in a low conductance mode. The Ca2+ fluxes taking place during mCICR are a direct consequence of the mitochondrial depolarization spike (mDPS) caused by PTP opening. Both mDPS and mCICR can propagate from one mitochondrion to another in vitro, generating traveling depolarization and Ca2+ waves. Mitochondria thus appear to be excitable organelles capable of generating and conveying electrical and Ca2+ signals. In living cells, mDPS/mCICR is triggered during IP3-induced Ca2+ mobilization and results in the amplification of the Ca2+ signals primarily emitted from the endoplasmic reticulum.

Animals↗
PubMed2001

Antidepressant activity and calcium signaling cascades.

Although antidepressant treatments produce clear effects on monoaminergic neuronal function, the link between these effects and therapeutic response to treatment is controversial. Previous studies have demonstrated that antagonists of the NMDA receptor-gated calcium ionophore result in antidepressant-like responses in rodents and humans. Likewise, antidepressant treatments produce regionally selective adaptation of the NMDA receptor suggestive of diminished capacity to gate calcium into receptive neurons. Similarly, voltage-dependent calcium channel antagonists have been reported to produce antidepressant-like effects in rodents. A major target of increases in subcellular calcium concentration is nitric oxide synthase (NOS) which liberates NO in response to stimulation. Recently, we have demonstrated that nitric oxide synthase antagonists produced antidepressant-like response in both in vivo preclinical screening procedures and in post-mortem in vitro studies of beta-adrenoceptor density. We propose: 1) that interruption of the Ca(2+)-calmodulin-NOS-guanylyl cyclase subcellular signaling pathway at any point will produce antidepressant-like effects; 2) that the acute actions of antidepressants in preclinical screening procedures are a consequence of their ability to disrupt Ca(2+)-calmodulin-NOS-guanylyl cyclase signaling; 3) that chronic but, not acute treatment with antidepressants results in adaptation of the Ca(2+)-calmodulin-NOS-guanylyl cyclase signaling pathway; 4) that this adaptation is necessary for the achievement of the therapeutic actions of antidepressants and; 5) that major depression is accompanied by an alteration (hyperactivity?) of subcellular Ca(2+) signaling. Copyright 2001 John Wiley & Sons, Ltd.

Journal Article↗
PubMed1996

Paracrine mediation of calcium signaling in human SK-N-MCIXC neuroepithelioma cells.

Paracrine-mediated Ca2+ signaling in SK-N-MCIXC neuroepithelioma cells was evaluated by means of two experimental paradigms. In the first, single SK-N-MCIXC cells were microinjected with inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and cytoplasmic Ca2+ was monitored by fura 2 digital-imaging microfluorometry. In response to Ins(1,4,5)P3 or CaCl2, but not inositol 1,3,4-trisphosphate, an increase in cytoplasmic Ca2+ concentration ([Ca2+]i) was observed in injected cells and also in neighboring cells. The direction of intercellular propagation of Ca2+ signals was influenced by the presence of a flow in the extracellular medium and occurred in the absence of any detectable gap-junctional communication. The P2 purinoceptor antagonist suramin, but not antagonists of other phosphoinositide-linked receptors, blocked cell-to-cell Ca2+ signaling initiated by microinjections of Ins(1,4,5)P3. In the second paradigm, conditioned medium (CM) obtained from monolayers of SK-N-MCIXC cells elicited increases in [Ca2+]i when reapplied to cells on coverslips. The Ca(2+)-mobilizing activity of CM was reversibly antagonized by suramin and abolished by pretreatment with apyrase. The presence of nucleotide di- and triphosphates in CM was confirmed by high-performance liquid chromatography. We conclude that SK-N-MCIXC cells release nucleotides that then activate specific receptors on neighboring cells. A rise in [Ca2+]i in these cells, and subsequent additional release of nucleotides, serves to further the propagation of intercellular Ca2+ signals.

Biological Transport↗
PubMed1998

Effect of CRF and related peptides on calcium signaling in human and rodent melanoma cells.

Corticotropin releasing factor (CRF) induces a rapid, within seconds, and dose-dependent increase in the intracellular Ca2+ in both human and hamster melanoma cells. This effect is inhibited by depletion of extracellular calcium using 3 mM EGTA and is attenuated by the CRF receptor antagonist, alpha-helical-CRF(9-41). Other peptides of the CRF superfamily, sauvagine and urocortin, also induce increases in cytoplasmic calcium concentration but at higher concentrations than CRF. We conclude that malignant melanocytes express CRF receptors, which are coupled to activation of plasma membrane calcium channels.

Amphibian Proteins↗
PubMed1996

Localized calcium signaling in multinucleated osteoclasts.

Localized intracellular Ca2+ ([Ca2+]i) pulses, fluctuations, and repetitive spikes were detected in multinucleated rabbit osteoclasts in the presence of serum and in response to calcitonin using the fluorescent calcium indicator fluo-3 and a laser scanning microscope. We observed that these [Ca2+], changes were often restricted within a region of the cell body or propagated from the initial region of occurrence to other parts of the cell body but not to all parts. These observations suggest the existence of significant barriers to Ca2+ transport between different cytoplasmic regions of the osteoclast. To further investigate this phenomenon, we mechanically perturbed different cellular regions by touching locally with a micropipette. This usually induced a local increase in cytosolic and nuclear free [Ca2+]i. In some cases there was propagation of the [Ca2+]i increase to other regions but with part of the cell body not affected. Those regions of the cell body to which the [Ca2+]i increase did not propagate had a [Ca2+]i response to a direct mechanical perturbation. Our data show that osteoclasts can have different [Ca2+]i activities in apparently equivalent cellular regions, no matter how generated. This suggests that there can be a number of spatially separate Ca2+ regulatory systems within an osteoclast cell body.

Animals↗
PubMed2001

Estradiol-induced nongenomic calcium signaling regulates genotropic signaling in macrophages.

Estradiol (E(2)) exerts not only genotropic but also nongenomic actions through nuclear estrogen receptors (ER). Here, we provide a novel paradigm for nongenomic E(2) signaling independent of nuclear ER. E(2) induces a rapid rise in the intracellular free Ca(2+) concentration ([Ca(2+)](i)) through membrane estrogen receptors in murine RAW 264.7 macrophages. This E(2)-induced Ca(2+) signaling is not prevented by different ER blockers and cannot directly activate stably transfected c-fos promoter or the mitogen-activated protein kinases p38, ERK1/2, and SAPK/JNK, or NO production. However, the E(2)-induced rise in [Ca(2+)](i) specifically down-regulates the serum-stimulated activation of c-fos promoter and ERK1/2, and conversely, it specifically up-regulates lipopolysaccharide-stimulated activation of c-fos promoter, p38, and NO production. The E(2)-changed activation of c-fos promoter can be prevented by an intracellular Ca(2+) chelator. Our data indicate that E(2)-induced nongenomic Ca(2+) signaling through membrane ER is able to specifically modulate genotropic signaling pathways with impact on macrophage activation.

Animals↗
PubMed1996

K+ channels and the intracellular calcium signal in human melanoma cell proliferation.

K+ channels, membrane voltage, and intracellular free Ca2+ are involved in regulating proliferation in a human melanoma cell line (SK MEL 28). Using patch-clamp techniques, we found an inwardly rectifying K+ channel and a calcium-activated K+ channel. The inwardly rectifying K+ channel was calcium independent, insensitive to charybdotoxin, and carried the major part of the whole-cell current. The K+ channel blockers quinidine, tetraethylammonium chloride and Ba2+ and elevated extracellular K+ caused a dose-dependent membrane depolarization. This depolarization was correlated to an inhibition of cell proliferation. Charybdotoxin affected neither membrane voltage nor proliferation. Basic fibroblast growth factor and fetal calf serum induced a transient peak in intracellular Ca2+ followed by a long-lasting Ca2+ influx. Depolarization by voltage clamp decreased and hyperpolarization increased intracellular Ca2+, illustrating a transmembrane flux of Ca2+ following its electrochemical gradient. We conclude that K+ channel blockers inhibit cell-cycle progression by membrane depolarization. This in turn reduces the driving force for the influx of Ca2+, a messenger in the mitogenic signal cascade of human melanoma cells.

Animals↗
PubMed2004

Autocrine and paracrine calcium signaling by the CD38/NAD+/cyclic ADP-ribose system.

CD38, a multifunctional enzyme, generates two potent Ca2+-releasing signal metabolites, cyclic ADP-ribose (cADPR) and NAADP+, thereby upmodulating many important Ca2+-mediated cell functions. A topological paradox has long been recognized, as CD38 is an ectoenzyme, or an intravesicularly located enzyme in subcellular membrane vesicles, therefore apparently shielded from its substrate NAD+. Moreover, cADPR generated by CD38 should be unavailable to its target Ca2+ stores, the ryanodine receptors (RyR). We have solved this paradox by identifying some NAD+ and cADPR transmembrane transporters, whose interplay mediates a hitherto-unrecognized subcellular and intercellular trafficking of nucleotides that enhances intracellular Ca2+ ([Ca2+]i). Connexin 43 (Cx43) hemichannels mediate an equilibrative transport of NAD+ from the cytosol to the active site of CD38 (either ectocellular or intravesicular). Subsequent translocation of in situ-generated cADPR to reach the RyR is performed, (i) by CD38 itself (concentrative) or (ii) by nucleoside transporters (NT) (one equilibrative and three concentrative). Besides this autocrine mechanism, the same transporters also mediate intercellular (paracrine) trafficking. Thus, Cx43+ and CD38+ cells can provide cADPR to neighboring RyR+ parenchymal cells and enhance their [Ca2+]i levels and Ca2+-dependent functions accordingly. Examples of cADPR-responsive cells via paracrine processes include (i) smooth myocytes, (ii) 3T3 murine fibroblasts, (iii) hippocampal neurons, and (iv) human hemopoietic stem cells.

3T3 Cells↗
PubMed1997

Bergmann glial cells in situ express endothelinB receptors linked to cytoplasmic calcium signals.

The endothelin (ET) isoforms ET-1, ET-2 and ET-3 applied at 100 nM triggered a transient increase in [Ca2+]i in Bergmann glial cells in cerebellar slices acutely isolated from 20-25 day-old mice. The intracellular calcium concentration ([Ca2+]i) was monitored using Fura-2-based [Ca2+]i microfluorimetry. The ET-triggered [Ca2+]i transients were mimicked by ETB receptor agonist BQ-3020 and were inhibited by ETB receptor antagonist BQ-788. ET elevated [Ca2+]i in Ca(2+)-free extracellular solution and the ET-triggered [Ca2+]i elevation was blocked by 500 nM thapsigargin indicating that the [Ca2+]i was released from InsP3-sensitive intracellular pools. The ET-triggered [Ca2+]i increase in Ca(2+)-free solution was shorter in duration. Restoration of normal extracellular [Ca2+] briefly after the ET application induced a second [Ca2+]i increase indicating the presence of a secondary Ca2+ influx which prolongs the Ca2+ signal. Pre-application of 100 microM ATP or 10 microM noradrenaline blocked the ET response suggesting the involvement of a common Ca2+ depot. The expression of ETB receptor mRNAs in Bergmann glial cells was revealed by single-cell RT-PCR. The mRNA was also found in Purkinje neurones, but no Ca2+ signalling was triggered by ET. We conclude that Bergmann glial cells are endowed with functional ETB receptors which induce the generation of intracellular [Ca2+]i signals by activation of Ca2+ release from InsP3-sensitive intracellular stores followed by a secondary Ca2+ influx.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1997

Arachidonic acid-induced calcium signalling in human airway smooth muscle cells.

The spatiotemporal distribution of Ca2+ signals evoked by arachidonic acid (AA) was investigated in human bronchial smooth muscle cells (SMC), using the single cell video imaging technique and Fura-2 as a fluorescent dye. Baseline Ca2+ levels were markedly heterogeneous in one and the same cell; the local Ca2 concentration laid between 90 +/- 11 and 215 +/- 18 nM (n = 15). AA (2 mM) induced propagating Ca2+ waves, travelling at a mean velocity of 18 +/- 3 microns/sec (n = 7). Ca2+ signals originated at discrete trigger zones, whose kinetic properties differed from those of neighbouring regions. Ca2+ in the trigger zones rose in two phases, with rates of 9.5 +/- 0.8 and 88 +/- 6 nM/sec (n = 17). A single cell frequently exhibited more than one trigger zones. In some cells, the wave did not reach all regions; such inert zones separated functionally the cell in independently active regions. Some regions presented Ca2+ signals that did not spread to the rest of the cell, forming isolated foci. The spatiotemporal variability of Ca2+ signals evoked by AA could result from the heterogeneity of Ca2+ homeostatic processes.

Arachidonic Acid↗
PubMed1994

Agonist-specific calcium signaling and phosphoinositide hydrolysis in human SK-N-MCIXC neuroepithelioma cells.

Fura-2 digital imaging microfluorimetry was used to evaluate the Ca2+ signals generated in single clonal human neuroepithelioma cells (SK-N-MCIXC) in response to agonists that stimulate phosphoinositide hydrolysis. Addition of optimal concentrations of either endothelin-1 (ET-1), ATP, oxotremorine-M (Oxo-M), or norepinephrine (NE) all resulted in an increase in the concentration of cytosolic calcium (Ca2+i) but of different magnitudes (ET-1 = ATP > Oxo-M > NE). The Ca2+ signals elicited by the individual agonists also differed from each other in terms of their latency of onset, rate of rise and decay, and prevalence of a sustained phase of Ca2+ influx. The Ca2+ signals that occurred in response to ATP had a shorter latency and more rapid rates of rise and decay than those observed for the other three agonists. Furthermore, a sustained plateau phase of the Ca2+ signal, which was characteristic of the response to Oxo-M, was observed in < 40% of cells stimulated with ET-1 and absent from Ca2+ signals elicited after NE addition. Removal of extracellular Ca2+ enhanced the rate of decay of Ca2+ signals generated by ATP, ET-1, or Oxo-M and, when evident, abolished the sustained phase of Ca2+ influx. In the absence of extracellular Ca2+, NE elicited asynchronous multiple Ca2+ transients. In either the absence or presence of extracellular Ca2+-, > 94% of cells responded to ET-1 or ATP, whereas corresponding values for Oxo-M and NE were approximately 74 and approximately 48%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed2003

Early changes in pancreatic acinar cell calcium signaling after pancreatic duct obstruction.

Intracellular Ca(2+)-changes not only participate in important signaling pathways but have also been implicated in a number of disease states including acute pancreatitis. To investigate the underlying mechanisms in an experimental model mimicking human gallstone-induced pancreatitis, we ligated the pancreatic duct of Sprague-Dawley rats and NMRI mice for up to 6 h and studied intrapancreatic changes including the dynamics of [Ca(2+)](i) in isolated acini. In contrast to bile duct ligation, pancreatic duct obstruction induced intra-pancreatic trypsinogen activation, leukocytosis, hyperamylasemia, and pancreatic edema and increased lung myeloperoxidase activity. Although resting [Ca(2+)](i) in isolated acini rose by 45% to 205 +/- 7 nmol, the acetylcholine- and cholecystokinin (CCK)-stimulated calcium peaks as well as the amylase secretion declined, but neither the [Ca(2+)](i)-signaling pattern nor the amylase output in response to the Ca(2+)-ATPase inhibitor thapsigargin nor the secretin-stimulated amylase release were impaired by pancreatic duct ligation. On the single cell level pancreatic duct ligation reduced the percentage of cells in which submaximal secretagogue stimulation was followed by a physiological response (i.e. Ca(2+) oscillations) and increased the percentage of cells with a pathological response (i.e. peak plateau or absent Ca(2+) signal). Moreover, it reduced the frequency and amplitude of Ca(2+) oscillation as well as the capacitative Ca(2+) influx in response to secretagogue stimulation. Serum pancreatic enzyme elevation as well as trypsinogen activation was significantly reduced by pretreatment of animals with the calcium chelator BAPTA-AM. These experiments suggest that pancreatic duct obstruction rapidly changes the physiological response of the exocrine pancreas to a Ca(2+)-signaling pattern that has been associated with premature digestive enzyme activation and the onset of pancreatitis, both of which can be prevented by administration of an intracellular calcium chelator.

Adenosine Triphosphatases↗