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At least 1,063 records · Page 59Linked to original sources
PubMed1992

Spiral waves and intracellular calcium signalling.

Confocal imaging of intracellular Ca2+ brings a new level of resolution to the study of hormonal control of intracellular Ca2+ release. This approach has demonstrated the existence of pulsatile circular and spiral waves of Ca+ release induced by receptor activation. The data obtained by confocal imaging support a new framework for understanding intracellular Ca2+ signalling. The goal of this chapter is to review our data on the complexity of intracellular Ca2+ release in Xenopus oocytes, introduce the concept of Ca2+ excitability as a model for Ca2+ release and discuss the implications for encoding intracellular signal information.

Animals↗
PubMed2000

The role of intracellular calcium signaling in premature protease activation and the onset of pancreatitis.

The exocrine pancreas synthesizes and secretes large amounts of digestive proteases as inactive precursor zymogens. Under physiological conditions a variety of cellular defense mechanisms protect the pancreatic acinar cell against a premature and intracellular activation of these zymogens. When these defenses fail, pancreatic autodigestion is initiated and acute pancreatitis can develop. A number of experimental observations suggest that extra- as well as intracellular calcium concentrations play an important part in the initiation of pancreatic protease activation, but the intracellular signaling events that regulate this process are unknown. Using a model system in which we used pancreatic acini (freshly prepared functional units of living acinar cells), we were able to simulate the conditions found during experimental pancreatitis in rodents. By means of a cell permeant fluorescent trypsin substrate we could demonstrate in these acini that premature protease activation is initiated at the apical acinar cell pole and occurs only in the presence of secretagogue concentrations that exceed those required for a maximum secretory response. By combining this technique with fluorescence ratio imaging for the Ca(2+)-sensitive dye fura-2, we could further show that this protease activation is highly dependent on the spatial as well as the temporal distribution of the corresponding Ca(2+) release from stores within the same subcellular compartment and that it is not propagated to neighboring acinar cells.

Animals↗
PubMed2006

Calcium signaling in non-excitable cells: Ca2+ release and influx are independent events linked to two plasma membrane Ca2+ entry channels.

The regulatory mechanism of Ca2+ influx into the cytosol from the extracellular space in non-excitable cells is not clear. The "capacitative calcium entry" (CCE) hypothesis suggested that Ca2+ influx is triggered by the IP(3)-mediated emptying of the intracellular Ca2+ stores. However, there is no clear evidence for CCE and its mechanism remains elusive. In the present work, we have provided the reported evidences to show that inhibition of IP(3)-dependent Ca2+ release does not affect Ca2+ influx, and the experimental protocols used to demonstrate CCE can stimulate Ca2+ influx by means other than emptying of the Ca2+ stores. In addition, we have presented the reports showing that IP(3)-mediated Ca2+ release is linked to a Ca2+ entry from the extracellular space, which does not increase cytosolic [Ca2+] prior to Ca2+ release. Based on these and other reports, we have provided a model of Ca2+ signaling in non-excitable cells, in which IP(3)-mediated emptying of the intracellular Ca2+ store triggers entry of Ca2+ directly into the store, through a plasma membrane TRPC channel. Thus, emptying and direct refilling of the Ca2+ stores are repeated in the presence of IP(3), giving rise to the transient phase of oscillatory Ca2+ release. Direct Ca2+ entry into the store is regulated by its filling status in a negative and positive manner through a Ca2+ -binding protein and Stim1/Orai complex, respectively. The sustained phase of Ca2+ influx is triggered by diacylglycerol (DAG) through the activation of another TRPC channel, independent of Ca2+ release. The plasma membrane IP(3) receptor (IP(3)R) plays an essential role in Ca2+ influx, by interacting with the DAG-activated TRPC, without the requirement of binding to IP(3).

Animals↗
PubMed2003

LAT links the pre-BCR to calcium signaling.

SLP-65(-/-) mice display a partial block at the pre-B cell stage of development. Here, we show that LAT is required for the differentiation of SLP-65(-/-) pre-B cells. We show that LAT and SLP-76 are recruited to the pre-BCR and associated with Ig-alpha upon pre-BCR engagement, whereas LAT interaction with SLP-76 is already detected in untreated pre-B cells. Reconstitution of LAT or SLP-65 expression in SLP-65/LAT(-/-) pre-B cells restored their calcium (Ca2+) mobilization capacity, led to downregulation of surface pre-BCR, and induced differentiation to BCR+ cells. Together, our results suggest that the adaptor proteins LAT and SLP-76 are involved in pre-BCR signaling, thereby rescuing arrested murine SLP-65(-/-) pre-B cells.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Vasopressin-induced neurotrophism in cultured neurons of the cerebral cortex: dependency on calcium signaling and protein kinase C activity.

Neuronal process outgrowth has been postulated to be one of the fundamental steps involved in neuronal development. To test whether vasopressin can influence neuronal development by acting on the outgrowth of neuronal processes, we determined the neurotrophic action of the memory-enhancing peptide, vasopressin, in neurons derived from the cerebral cortex, a site of integrative cognitive function and long-term memory. Exposure to V(1) receptor agonist significantly increased multiple features of nerve cell morphology, including neurite length, number of branches, branch length, number of branch bifurcation points and number of microspikes. The dose-response profile of V(1) receptor agonist-induced neurotrophism exhibited a biphasic function, with lower concentrations inducing a significant increase while higher concentrations generally induced no significant effect. The neurotrophic effect of V(1) receptor activation did not require growth factors present in serum. Analysis of the regional selectivity of the vasopressin-induced neurotrophic effect revealed significant V(1) receptor agonist-induced neurotrophism in occipital and parietal neurons, whereas frontal and temporal neurons were unresponsive. Results of experiments to determine the mechanism of vasopressin-induced neurotrophism demonstrated that vasopressin-induced neurotrophism is dependent on V(1)a receptor activation, requires L-type calcium channel activation and activation of both pathways of the phosphatidylinositol signaling cascade, inositol trisphosphate and protein kinase C. These studies are the first to describe a functional cellular response for vasopressin in the cerebral cortex. The findings are discussed with respect to their implications for understanding the role of vasopressin-induced neurotrophism, the associated signaling pathways required for this response, and the ability of vasopressin to enhance memory function.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2005

Novel compartment implicated in calcium signaling--is it an "induced coupling domain"?

The endoplasmic reticulum (ER) is not simply a uniform continuous organelle, but is spatially and functionally heterogeneous with nonuniform distribution of endoplasmic Ca(2+)-handling proteins, such as Ca(2+)-binding proteins, Ca(2+) pumps, and Ca(2+)-release channels. Such nonuniform distribution of Ca(2+)-handling proteins is thought to create a spatially divided calcium store and to contribute to the generation of complex intracellular Ca(2+) dynamics. In addition to the particular distribution of these Ca(2+)-handling proteins within ER, extracellular stimuli may also stimulate the formation of dynamic new ER compartments containing Ca(2+)-handling proteins. These compartments containing Ca(2+)-handling proteins have potential roles in Ca(2+) signaling; specifically, they may function as "induced coupling domains" between the ER and plasma membrane, thereby allowing Ca(2+) entry into the ER.

Animals↗
PubMed2004

Calcium signaling and polycystin-2.

Polycystic kidney disease (PKD) is caused by mutations in two genes, PKD1 and PKD2, which encode for the proteins, polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Although disease-associated mutations have been identified in these two proteins, the sequence of molecular events leading up to clinical symptoms is still unknown. PC1 resides in the plasma membrane and it is thought to function in cell-cell and cell-matrix interactions, whereas PC2 is a calcium (Ca2+) permeable cation channel concentrated in the endoplasmic reticulum. Both proteins localize to the primary cilia where they function as a mechanosensitive receptor complex allowing the entry of Ca2+ into the cell. The downstream signaling pathway involves activation of intracellular Ca2+ release channels, especially the ryanodine receptor (RyR), but subsequent steps are still to be identified. Elucidation of the signaling pathway involved in normal PC1/PC2 function, the functional consequences of PC1/PC2 mutation, and the role of Ca2+ signaling will all help to unravel the molecular mechanisms of cystogenesis in PKD.

Animals↗
PubMed1994

Glutamate-induced calcium signaling in astrocytes.

Astrocytes respond to the excitatory neurotransmitter glutamate with dynamic spatio-temporal changes in intracellular calcium [Ca2+]i. Although they share a common wave-like appearance, the different [Ca2+]i changes--an initial spike, sustained elevation, oscillatory intracellular waves, and regenerative intercellular waves--are actually separate and distinct phenomena. These separate components of the astrocytic Ca2+ response appear to be generated by two different signal transduction pathways. The metabotropic response evokes an initial spatial Ca2+ spike that can propagate rapidly from cell to cell and appears to involve IP3. The metabotropic response can also produce oscillatory intracellular waves of various amplitudes and frequencies that propagate within cells and are sustained only in the presence of external Ca2+. The ionotropic response, however, evokes a sustained elevation in [Ca2+]i associated with receptor-mediated Na+ and Ca2+ influx, depolarization, and voltage-dependent Ca2+ influx. In addition, the ionotropic response can lead to regenerative intercellular waves that propagate smoothly and nondecrementally from cell to cell, possibly involving Na+/Ca2+ exchange. All these astrocytic [Ca2+]i changes tend to appear wave-like, traveling from region to region as a transient rise in [Ca2+]i. Nevertheless, as our understanding of the cellular events that underlie these [Ca2+]i changes grows, it becomes increasingly clear that glutamate-induced Ca2+ signaling is a composite of separate and distinct phenomena, which may be distinguished not based on appearance alone, but rather on their underlying mechanisms.

Animals↗
PubMed1995

Subcellular organization of calcium signalling in hepatocytes and the intact liver.

Hepatocytes respond to inositol 1,4,5-trisphosphate (InsP3)-linked agonists with frequency-modulated oscillations in the intracellular free calcium concentration ([Ca2+]i), that occur as waves propagating from a specific origin within each cell. The subcellular distribution and functional organization of InsP3-sensitive Ca2+ pools has been investigated, in both intact and permeabilized cells, by fluorescence imaging of dyes which can be used to monitor luminal Ca2+ content and InsP3-activated ion permeability in a spatially resolved manner. The Ca2+ stores behave as a luminally continuous system distributed throughout the cytoplasm. The structure of the stores, an important determinant of their function, is controlled by the cytoskeleton and can be modulated in a guanine nucleotide-dependent manner. The nuclear matrix is devoid of Ca2+ stores, but Ca2+ waves in the intact cell propagate through this compartment. The organization of [Ca2+]i signals has also been investigated in the perfused liver. Frequency-modulated [Ca2+]i oscillations are still observed at the single cell level, with similar properties to those in the isolated hepatocyte. The [Ca2+]i oscillations propagate between cells in the intact liver, leading to the synchronization of [Ca2+]i signals across part or all of each hepatic lobule.

Animals↗
PubMed2005

Extracellular group A Streptococcus induces keratinocyte apoptosis by dysregulating calcium signalling.

Group A Streptococcus (GAS) colonizes the oropharynx and damaged skin. To cause local infection or severe invasive syndromes the bacteria must gain access into deeper tissues. Host cell death may facilitate this process. GAS internalization has been identified to induce apoptosis. We now report an alternate mechanism of GAS-mediated apoptosis of primary human keratinocytes, initiated by extracellular GAS and involving dysregulation of intracellular calcium to produce endoplasmic reticulum stress. Two bacterial virulence factors are required for effective induction of apoptosis by extracellular GAS: (i) hyaluronic acid capsule that inhibits bacterial internalization and (ii) secreted cytolysin, streptolysin O (SLO), that forms transmembrane pores that permit extracellular calcium influx into the cytosol. Induction of keratinocyte apoptosis by wild-type GAS was accompanied by cell detachment and loss of epithelial integrity, a phenomenon not observed with GAS deficient in capsule or SLO. We propose that cell signalling initiated by extracellular GAS compromises the epithelial barrier by inducing premature keratinocyte differentiation and apoptosis, thereby facilitating GAS invasion of deeper tissues.

Apoptosis↗
PubMed2005

Effects of sphingosine 1-phosphate on calcium signaling, proliferation and S1P2 receptor expression in PC Cl3 rat thyroid cells.

Sphingosine 1-phosphate (S1P) regulates diverse biological processes, including mitosis, by binding to the S1P family of G-protein coupled receptors. The aim of the study was to determine the pattern of S1P receptor expression and to investigate the effects of S1P on intracellular calcium levels and proliferation in the rat thyroid cell line PC Cl(3). S1P(2) and S1P(3) mRNA and proteins were detected in PC Cl(3) cells, as well as in FRTL-5 rat thyroid cells. In addition, S1P(5) mRNA was present at low levels, but not S1P(1) or S1P(4). In PC Cl(3) cells, S1P invoked calcium release from intracellular stores, but not calcium entry. The Ca(2+) release was mediated by phospholipase C and inositol 1,4,5-trisphosphate. S1P attenuated the TSH-evoked cAMP increase in a pertussis toxin-sensitive manner. S1P per se did not affect the proliferation of the cells, but attenuated the proliferation evoked by a combination of insulin and TSH. Furthermore, S1P attenuated the PMA-evoked proliferation. S1P(2) expression was positively regulated by insulin and PMA. S1P itself transiently upregulated S1P(2) receptor mRNA, while TSH had a net downregulating effect on S1P(2) expression. In summary, S1P modulates central intracellular signaling cascades and is antiproliferative in PC Cl(3) cells. S1P(2) receptor expression is modulated by insulin and TSH, two central growth factors in thyroid cell regulation.

Animals↗
PubMed1990

Generation and amplification of the cytosolic calcium signal during secretory responses to gonadotropin-releasing hormone.

Gonadotropin-releasing hormone (GnRH) stimulates characteristic biphasic increases in cytosolic calcium concentration ([Ca2+]i) and in luteinizing hormone (LH) release in cultured gonadotrophs, with an early peak followed by a prolonged plateau in both responses. Analysis of [Ca2+]i by dual-wavelength fluorimetric assay and of LH release at 5-sec intervals in perifused pituitary cells revealed increases in both responses within a few seconds of exposure to GnRH. The maximum elevation of [Ca2+]i occurred within 20 sec, and the peak gonadotropin release in 35 sec; the total duration of the spike phase for both [Ca2+]i and LH release was 2.5 min. Under extracellular Ca2(+)-deficient conditions, the GnRH-induced peak in [Ca2+]i was reduced by about 20% and the plateau phase was abolished. Concomitantly, the magnitude of the acute phase of LH release was reduced by 40% and that of the second phase by about 90%. Recovery of the plateau phase of LH release occurred within 25 sec after addition of 1.25 mM Ca2+ to Ca2(+)-deficient medium. In a dose-dependent manner, the non-selective Ca2+ channel blockers Co2+ and Cd2+ reduced the Ca2+ current measured by whole-cell recording in pituitary gonadotrophs and abolished the extracellular Ca2(+)-dependent component of LH release. The selective calcium channel blocker, nifedipine, decreased the magnitude of the Ca2+ current and reduced the plateau phase of LH release by 50%; conversely, the dihydropyridine agonist methyl, 1,4,dihydro-2,6-dimethyl 3-nitro-4-(2-trifluorome) (Bay K 8644) consistently enhanced the amplitudes of both Ca2+ current and GnRH-induced LH release. These data reveal a close temporal correlation between changes in [Ca2+]i and LH release during GnRH action, with Ca2+ mobilization during the spike phase and Ca2+ influx through dihydropyridine-sensitive and insensitive sets of receptor-operated calcium channels during the spike and plateau phases. In addition, analysis of the magnitudes of the [Ca2+]i and LH responses to a wide range of GnRH concentrations in the presence and absence of extracellular Ca2+ is consistent with amplification of the [Ca2+]i signal in agonist-stimulated gonadotrops.

Animals↗
PubMed1999

Neuroligand-mediated calcium signaling in cultured human schwannoma cells.

Intracellular Ca2+ release regulates proliferation of nonexcitable cells, however, it is not known whether and which neuroligands modulate the free intracellular Ca2+ concentration in human schwannoma cells. Confocal laser scanning microscopy was used for the study of neuroligand-induced Ca2+ signaling in cultured human schwannoma cells loaded with the Ca2+-sensitive fluorescent dyes Calcium Green-1 and Fura Red. Intracellular Ca2+ transients were observed during bath application of ATP (90% of cells tested), endothelin (60%), and norepinephrine (20%); histamine, serotonin, glutamate, and bradykinin did not have this effect. Two types of P2Y nucleotide receptor subtypes involved in ATP-induced Ca2+ transients could be separated by application of different P2Y receptor agonists and cross desensitization experiments: P2Y1 (rank order of potency: 2-MeSADP > 2-MeSATP > ADP > ATP) and P2Y2 (sensitive to UTP and ATP). Endothelin-induced Ca2+ signaling was also seen during application of [Ala(1,3,11,15)]ET-1; this suggests the presence of an ET(B) receptor subtype. The results indicate that the presence of receptors linked to neuroligand-triggered Ca2+ signaling does not seem to be abnormal in a human Schwann cell tumor, i.e. schwannoma cells retain this characteristic of peripheral glia.

Adenosine Diphosphate↗