Calcium signals and human oocyte activation: implications for assisted conception.
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Animals↗
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Sequential cytoplasmic calcium signals in a 2-stage platelet activation process induced by the glycoprotein Ibalpha mechanoreceptor.
We found that the interaction of platelets with immobilized von Willebrand factor (VWF) under flow induces distinct elevations of cytosolic Ca(++) concentration ([Ca(++)](i)) that are associated with sequential stages of integrin alpha(IIb)beta(3) activation. Fluid-dynamic conditions that are compatible with the existence of tensile stress on the bonds between glycoprotein Ibalpha (GPIbalpha) and the VWF A1 domain led to Ca(++) release from intracellular stores (type alpha/beta peaks), which preceded stationary platelet adhesion. Raised levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate, as well as membrane-permeable calcium chelators, inhibited these [Ca(++)](i) oscillations and prevented stable adhesion without affecting the dynamic characteristics of the typical platelet translocation on VWF mediated by GPIbalpha. Once adhesion was established through the integrin alpha(IIb)beta(3), new [Ca(++)](i) oscillations (type gamma) of greater amplitude and duration, and involving a transmembrane ion flux, developed in association with the recruitment of additional platelets into aggregates. Degradation of released adenosine diphosphate (ADP) to AMP or inhibition of phosphatidylinositol 3-kinase (PI3-K) prevented this response without affecting stationary adhesion and blocked aggregation. These findings indicate that an initial signal induced by stressed GPIbalpha-VWF bonds leads to alpha(IIb)beta(3) activation sufficient to support localized platelet adhesion. Then, additional signals from ADP receptors and possibly ligand-occupied alpha(IIb)beta(3), with the contribution of a pathway involving PI3-K, amplify platelet activation to the level required for aggregation. Our conclusions modify those proposed by others regarding the mechanisms that regulate signaling between GPIbalpha and alpha(IIb)beta(3) and lead to platelet adhesion and aggregation on immobilized VWF.
Androstadienes↗
Different patterns of calcium signaling triggered through two components of the B lymphocyte antigen receptor.
The engagement of the B cell antigen receptor is the first step of antigenic stimulation of B lymphocytes. This step is followed by a series of biochemical events, including the activation of protein-tyrosine kinases, phosphoinositide turnover, and multiple patterns of calcium mobilization, which lead to the regulation of gene transcription and cellular responses. The B cell antigen receptor complex is composed of membrane immunoglobulins (as antigen recognition subunits) and associated chains (Ig-alpha and Ig-beta) that couple the receptor to cytoplasmic protein kinases. To investigate independently the relative signaling capacity of Ig-alpha and Ig-beta, chimeric proteins containing their cytoplasmic domains were expressed in a B cell line. We found that Ig-alpha and Ig-beta activate two distinct intracellular signaling pathways. The engagement of Ig-alpha chimeras induces a complete release of calcium from intracellular stores, followed by transmembrane calcium influx and late cell activation signals, detected by lymphokine secretion. In contrast, Ig-beta chimeras do not induce lymphokine secretion or calcium influx, but induce short oscillatory release of calcium, dependent on the activity of the Ca-ATPase pump of the endoplasmic reticulum. These results provide a structural basis for the diversity of B cell responses.
B-Lymphocytes↗
Programmed cell death-involved aluminum toxicity in yeast alleviated by antiapoptotic members with decreased calcium signals.
The molecular mechanisms of aluminum (Al) toxicity and tolerance in plants have been the focus of ongoing research in the area of stress phytophysiology. Recent studies have described Al-induced apoptosis-like cell death in plant and animal cells. In this study, we show that yeast (Saccharomyces cerevisiae) exposed to low effective concentrations of Al for short times undergoes enhanced cell division in a manner that is dose and cell density dependent. At higher concentrations of Al or longer exposure times, Al induces cell death and growth inhibition. Several apoptotic features appear during Al treatment, including cell shrinkage, vacuolation, chromatin marginalization, nuclear fragmentation, DNA degradation, and DNA strand breaks, as well as concomitant cell aggregation. Yeast strains expressing Ced-9, Bcl-2, and PpBI-1 (a plant Bax inhibitor-1 isolated from Phyllostachys praecox), respectively, display more resistance to Al toxicity compared with control cells. Data from flow cytometric studies show these three antiapoptotic members do not affect reactive oxygen species levels, but decrease calcium ion (Ca(2+)) signals in response to Al stress, although both intracellular reactive oxygen species and Ca(2+) levels were increased. The data presented suggest that manipulation of the negative regulation process of programmed cell death may provide a novel mechanism for conferring Al tolerance.
Aluminum↗
Inositol phosphate metabolism and its relationship to calcium signalling.
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Animals↗
Regulatory and spatial aspects of inositol trisphosphate-mediated calcium signals.
Hormones that act to release Ca2+ from intracellular stores initiate a signaling cascade that culminates in the production of inositol 1,4,5-trisphosphate (InsP3). The Ca2+ response mediated by InsP3 is not a sustained increase in the cytosolic Ca2+ concentration, but rather a series of periodic spikes that manifest as waves in larger cells. In vitro studies have determined that the key positive feedback parameter driving spikes and waves is a highly localized direct Ca(2+)-activation of InsP3-gated Ca2+ channels. Advances in fluorescent Ca2+ imaging have facilitated the resolution of individual positive feedback units. These studies have revealed that there are several modes of channel coupling underlying global Ca2+ signals; single channel openings or Ca2+ "blips," synchronized clusters of channels or Ca2+ "puffs," and cell wide calcium waves. It appears that the channel clusters that produce Ca2+ puffs are synchronized by the highly localized positive feedback that was predicted by the in vitro studies of channel regulation. Localization of InsP3-induced Ca2+ signals has been shown to be important for activation of several cellular processes including uni-directional salt flow and mitochondrial activation.
Animals↗
Testosterone regulates gonadotropin-releasing hormone-induced calcium signals in male rat gonadotrophs.
As the GnRH-induced secretion of gonadotropins is critically dependent upon an increase in the intracellular calcium ion concentration ([Ca2+]i) and modulated by gonadal factors, the effects of gonadal steroids on the pattern of calcium mobilization in single gonadotrophs of the male rat were examined using the fluorescent Ca2+ indicator fura-2/AM. In cells from intact rats, low concentrations of GnRH induce repetitive oscillations in [Ca2+]i, whereas spike-plateau responses are observed at higher concentrations in single gonadotrophs. After castration, there was a significant change in the relationship between the GnRH concentration and the changes in [Ca2+]i. Increasing concentrations of GnRH (to 1 micron) generate fewer spike-plateau responses in gonadotrophs from castrate rats, with oscillatory responses predominating. This change develops with time after castration, with the proportion of cells oscillating in response to 100 nM GnRH peaking by 7 days. This effect of castration on GnRH-induced [Ca2+]i signals was reversed by treatment with testosterone propionate (100 microgram/100 g BW-day). Castration-induced decreases in serum testosterone, seminal vesicle, and prostate weights and increases in serum LH concentration were also corrected by testosterone propionate treatment. These findings demonstrate that testosterone regulates GnRH-stimulated Ca2+ signals in gonadotrophs and suggest that gonadal steroids exert a regulatory role in the secretion of gonadotropins at the level of Ca2+ mobilization.
Animals↗
Study of calcium signaling in cell cleavage using confocal microscopy.
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Animals↗
Follicle-stimulating hormone mediated calcium signaling by the alternatively spliced growth factor type I receptor.
Ovarian granulosa cell and testicular Sertoli cell functions are regulated by the tropic action of the pituitary follicle-stimulating hormone (FSH), which may exert pleiotropic effects using a variety of signaling pathways. The effects of FSH on the mobilization of Ca(2+) into granulosa and Sertoli cells have been widely studied, but whether all the effects of the hormone are mediated by the single G-protein-coupled (G(s)) receptor with the seven-transmembrane structure (R1) has remained an enigma. With the object of resolving this mystery, we have compared the hormonal responses of HEK 293 cells transfected with three different cloned FSH receptor cDNAs of testis/ovary, designated R1 (G(s)), R2 (similar to R1 but having a shorter carboxyl terminus), and R3, a novel FSH receptor exhibiting a growth factor type I receptor motif. The latter two that use the same DNA segment for alternative splicing of the single large 80- to 100-kilobase gene create different structural motifs and carboxyl termini. Of the three receptors, only the FSH-R3 type induced a significant rise in intracellular free calcium concentration ([Ca(2+)](i)), as measured by single cell fluorescence digital imaging with the Ca(2+) sensitive dye fura-2AM. FSH induced a rapid [Ca(2+)](i) response that was concentration dependent. The response was hormone-specific, as neither its individual alpha/beta subunits nor the related glycoprotein hormone LH were effective. To determine whether the [Ca(2+)](i) response was due to Ca(2+) influx or to intracellular Ca(2+) mobilization, cells were exposed to Ca(2+)-free buffer and to the Ca(2+)-channel blocker diltiazem (10(-5) M). FSH-Induced [Ca(2+)](i) responses were inhibited in Ca(2+)-free buffer and abrogated in the presence of diltiazem. These novel data demonstrate that FSH can increase [Ca(2+)](i) through L-type voltage-dependent Ca(2+) channels via the growth factor type 1 receptor. Our findings support the concept that different receptor motifs act to integrate intracellular signaling events.
Alternative Splicing↗
Differences between rats and rabbits in NMDA receptor-mediated calcium signalling in hippocampal neurones.
In vivo microdialysis combined with the measurement of (45)Ca(2+) efflux from prelabelled hippocampus demonstrated a pronounced N-methyl-D-aspartate (NMDA)-evoked (45)Ca(2+) release to the dialysate in the rat dentate gyrus (DG) and CA1, whereas in rabbit a slight release of (45)Ca(2+) was observed only in the DG. In vitro, we noticed that the NMDA-evoked increase in Fura-2 detected intracellular Ca(2+) concentration in synaptoneurosomes from the rat, but not from the rabbit hippocampus, was strongly inhibited by the ryanodine receptor (RyR) antagonists dantrolene and ryanodine. To establish the mechanism of these differences, we characterised their possible dependence on the expression of RyR and their co-localisation with the calcium binding protein calbindin D(28k). A pronounced expression of [(3)H]ryanodine binding sites in the rat DG, which is only slight in the CA1, was demonstrated whereas in rabbit they were only found in the DG. The pattern of expression of calbindin D(28k) immunoreactivity and RyR in the rat and rabbit hippocampus was similar. These results suggest that the functional role of RyR in the generation of the NMDA receptor-mediated intracellular Ca(2+) signalling in the rabbit hippocampal neurones is marginal when compared to the rat. These differences reflect a diverse expression of RyR in both species. The corresponding differences in calbindin D(28k) immunoreactivity are most probably secondary in nature.
Animals↗
Cytokine-induced prostaglandin E2 production and cyclooxygenase-2 expression in dental pulp cells: downstream calcium signalling via activation of prostaglandin EP receptor.
AIM: To determine whether (i) proinflammatory cytokines stimulate prostaglandin E(2) (PGE(2)) production and cyclooxygenase (COX) gene expression in dental pulp cells, and (ii) pulp cells that express different prostaglandin E(2) receptor (EP) isoforms and their activation by PGE(2) leads to downstream Ca(2+) signalling. METHODOLOGY: Cultured human dental pulp cells were exposed to interleukin (IL)-1beta and tumour necrotic factor-alpha (TNF-alpha). The expression of COX-1 and COX-2 was measured with reverse transcriptase-polymerase chain reaction (RT-PCR). The production of PGE(2) was measured using an enzyme-linked immunosorbent assay. Expression of prostaglandin EP receptor isoforms was studied by RT-PCR, whereas fura-2 fluorescence was used to measure calcium mobilization. The Kruskal-Wallis test and Wilcoxon sum rank test with Bonferroni correction were used for statistical analysis. RESULTS: Interleukin-1beta and TNF-alpha stimulate PGE(2) production of human dental pulp cells (P < 0.05). IL-1beta stimulated the COX-2 but not COX-1 mRNA expression. Pulp cells express mainly EP2, EP3 and EP1 receptors as analysed by RT-PCR. PGE(2) (0.25-2 micromol L(-1)) stimulated the Ca(2+) mobilization as indicated by increase in fura-2 fluorescence. CONCLUSIONS: Interleukin-1beta and TNF-alpha may stimulate PGE(2) production in dental pulp cells. Activation of prostaglandin EP receptors in dental pulp cells by PGE(2) may induce Ca(2+) signalling to regulate cellular biological activity during inflammation.
Calcium Signaling↗
N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) does not modify the angiotensin II-stimulated calcium signal in cultured bovine glomerulosa cells.
Studies were performed to determine if the sustained elevation in [Ca2+]c noted previously in glomerulosa cells in response to Ang II resulted from the presence of HEPES in the experimental medium. At confluence, primary cultures of bovine glomerulosa cells were maintained for 24-30 h in the presence of either 14 mM NaHCO3/5% CO2 or 25 mM HEPES/4 mM NaHCO3/air. During subsequent experimental periods, cells were incubated in the presence of the corresponding or reciprocal buffer, and the effects of Ang II on [Ca2+]c were monitored by fura 2 fluorescence. Increases in [Ca2+]c produced by Ang II in cells continuously maintained in either HCO3(-) - or HEPES-buffered media were similar, and with the same monolayer the nature of the Ang II-stimulated Ca2+ signal was independent of the buffer employed. Moreover, the Ang II-stimulated Ca2+ signal was not significantly affected by the removal of HCO3- from the superfusate. These results indicate that the sustained increase in [Ca2+]c is not an artifact introduced by the use of HEPES as an experimental buffer, but rather a normal component of the Ang II-stimulated Ca2+ signal.
Aldosterone↗
Convergence of calcium signaling pathways of pathogenic elicitors and abscisic acid in Arabidopsis guard cells.
A variety of stimuli, such as abscisic acid (ABA), reactive oxygen species (ROS), and elicitors of plant defense reactions, have been shown to induce stomatal closure. Our study addresses commonalities in the signaling pathways that these stimuli trigger. A recent report showed that both ABA and ROS stimulate an NADPH-dependent, hyperpolarization-activated Ca(2+) influx current in Arabidopsis guard cells termed "I(Ca)" (Z.M. Pei, Y. Murata, G. Benning, S. Thomine, B. Klüsener, G.J. Allen, E. Grill, J.I. Schroeder, Nature [2002] 406: 731-734). We found that yeast (Saccharomyces cerevisiae) elicitor and chitosan, both elicitors of plant defense responses, also activate this current and activation requires cytosolic NAD(P)H. These elicitors also induced elevations in the concentration of free cytosolic calcium ([Ca(2+)](cyt)) and stomatal closure in guard cells. ABA and ROS elicited [Ca(2+)](cyt) oscillations in guard cells only when extracellular Ca(2+) was present. In a 5 mM KCl extracellular buffer, 45% of guard cells exhibited spontaneous [Ca(2+)](cyt) oscillations that differed in their kinetic properties from ABA-induced Ca(2+) increases. These spontaneous [Ca(2+)](cyt) oscillations also required the availability of extracellular Ca(2+) and depended on the extracellular potassium concentration. Interestingly, when ABA was applied to spontaneously oscillating cells, ABA caused cessation of [Ca(2+)](cyt) elevations in 62 of 101 cells, revealing a new mode of ABA signaling. These data show that fungal elicitors activate a shared branch with ABA in the stress signal transduction pathway in guard cells that activates plasma membrane I(Ca) channels and support a requirement for extracellular Ca(2+) for elicitor and ABA signaling, as well as for cellular [Ca(2+)](cyt) oscillation maintenance.
Abscisic Acid↗
Separate 5-hydroxytryptamine receptors on the salivary gland of the blowfly are linked to the generation of either cyclic adenosine 3',5'-monophosphate or calcium signals.
1 5'-Hydroxytryptamine (5-HT) stimulates the formation of two separate second messengers in the salivary gland of the blowfly. Activation of adenylate cyclase raises adenosine 3',5'-monophosphate (cyclic AMP) whereas the hydrolysis of phosphatidylinositol (PI) is associated with an increase in calcium permeability. The possibility that these two signal pathways might be controlled by separate 5-HT receptors was studied by testing the specificity of 5-HT analogues and antagonists. 2 The parent compound 5-HT was found to stimulate both cyclic AMP formation and the related parameters of PI hydrolysis and calcium transport with similar dose-response relationships. 3 Certain analogues such as 4- and 5-fluoro-alpha-methyltryptamine were capable of raising cyclic AMP levels and stimulating fluid secretion but did not stimulate the hydrolysis of PI or the entry of calcium. 4 Other analogues, which had chloro or methyl substituents at the 5-position, were found to stimulate the hydrolysis of PI and the transport of calcium at much lower doses than those required to stimulate the formation of cyclic AMP. 5 Antagonists were also found to exert selective effects. Methysergide was a potent inhibitor of PI hydrolysis whereas cinanserin was far more selective in blocking the stimulatory effect of 5-HT on cyclic AMP formation. 6 It is concluded that 5-HT acts on two separate receptors, a 5-HT1 receptor acting through calcium and a 5-HT2 receptor which mediates its effects through cyclic AMP.
Animals↗
Modulation by food restriction of intracellular calcium signaling in parotid acinar cells of aging Fischer 344 rats.
Previous studies suggest that alpha 1-adrenergic (alpha 1-AR)-induced intracellular calcium ([Ca2+]i) mobilization in rat parotid acinar cells declines with age. In this study, we examined the effects of food restriction on alpha 1-AR and muscarinic-stimulated [Ca2+]i mobilization in parotid acinar cells during aging. [Ca2+]i levels in response to the alpha 1-AR agonist epinephrine and the muscarinic agonist carbachol were evaluated in Fura-2-loaded parotid acinar cells from ad libitum-fed (AL) and food-restricted (FR) Fischer 344 male rats at 4, 6, 14, and 24 months of age. [Ca2+]i responses to epinephrine and carbachol (10 microM) were significantly reduced (48% and 35%, respectively; p < .05) in cells from 24-month-old AL rats as compared to younger AL rats. In contrast, no significant reduction of epinephrine and carbachol responses was observed in 24-month-old FR animals. An age-related increase in basal [Ca2+]i (peak around 14 months; p < .02) was observed in both AL and FR rats. In addition, basal [Ca2+]i was higher in FR than in AL rats at 14 and 24 months of age (p < .02). These studies suggest that FR partially attenuates or delays age-related impairments in alpha 1-AR- and muscarinic-cholinergic signal transduction systems of parotid acinar cells. Basal [Ca2+]i also appears to be altered during aging and by FR.
Adrenergic Agonists↗
Modulation of calcium signals by intracellular pH in isolated rat pancreatic acinar cells.
1. We have investigated the interactions between intracellular pH (pH1) and the intracellular free calcium concentration ([Ca2+]i) in isolated rat pancreatic acinar cells. The fluorescent dyes fura-2 and BCECF were used to measure [Ca2+]i and pHi, respectively. 2. Sodium acetate and ammonium chloride (NH4Cl) were used to acidify and alkalinize pHi, respectively. Cytosolic acidification had no effect on [Ca2+]i in resting pancreatic acinar cells, whereas cytosolic alkalinization released Ca2+ from intracellular stores. 3. Cytosolic acidification using either acetate or a CO2-HCO3(-)-buffered medium enhanced Ca2+ signals evoked by acetylcholine (ACh) and cholecystokinin (CCK). In contrast, both NH4Cl and trimethylamine (TMA) inhibited Ca2+ signals during stimulation with either ACh or CCK. This inhibitory effect was also observed in the absence of extracellular Ca2+, and was therefore not due to changes in Ca2+ entry. 4. Calcium oscillations evoked by physiological concentrations of CCK were enhanced by cytosolic acidification and inhibited by cytosolic alkalinization. 5. In order to determine the effects of pHi upon Ca2+ handling by intracellular Ca2+ stores, intraorganellar [Ca2+] was monitored using the low affinity Ca2+ indicator mag-fura-2 in permeabilized cells. Addition of NH4Cl, which is expected to alkalinize intraorganellar pH, did not alter intraorganellar [Ca2+] in permeabilized cells, suggesting that changing intraorganellar pH does not release Ca2+ from intracellular stores. Addition of NH4Cl or acetate also did not affect the rate of Ca2+ release induced by inositol 1,4,5-trisphosphate (InsP3). 6. Modification of extraorganellar ('cytosolic') pH did not affect the rate of ATP-dependent Ca2+ uptake into stores, but did modify the rate of Ca2+ release evoked by submaximal concentrations of InsP3. The rate of Ca2+ release was increased at more alkaline extraorganellar pHs. These results would suggest that manipulation of intraorganellar pH does not affect Ca2+ handling by the intracellular stores. In contrast, extraorganellar ('cytosolic') pH does affect InsP3-induced Ca2+ release from the stores. 7. In conclusion, changes in intracellular pH in pancreatic acinar cells can profoundly alter cytosolic [Ca2+]. This may shed light on earlier observations whereby cell-permeant weak acids and bases can modulate fluid secretion in epithelia.
Acetates↗
TGF-beta1 calcium signaling in osteoblasts.
Transforming growth factor-beta1 (TGF-beta1) action is known to be initiated by its binding to multiple cell surface receptors containing serine/threonine kinase domains that act to stimulate a cascade of signaling events in a variety of cell types. We have previously shown that TGF-beta1 and BMP-2 treatment of primary human osteoblasts (HOBs) enhances cell-substrate adhesion. In this report, we demonstrate that TGF-beta1 elicits a rapid, transient, and oscillatory rise in the intracellular Ca(2+) concentration, [Ca(2+)](i), that is necessary for enhancement of cell adhesion in HOBs but does not alter the phosphorylation state of Smad proteins. This rise in [Ca(2+)](i) in HOB is not observed in the absence of extracellular calcium or when the cells are treated with the L-type Ca(2+) channel blocker, nifedipine, but is stimulated upon treatment with the L-type Ca(2+) channel agonist, Bay K 8644, or under high K(+) conditions. The rise in [Ca(2+)](i) is severely attenuated after treatment of the cells with thapsigargin, a selective endoplasmic reticulum Ca(2+) pump inhibitor. TGF-beta1 enhancement of HOB adhesion to tissue culture polystyrene is also inhibited in cells treated with nifedipine. These data suggest that intracellular Ca(2+) signaling is an important second messenger of the TGF-beta1 signal transduction pathway in osteoblast function.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Integrating cytosolic calcium signals into mitochondrial metabolic responses.
Stimulation of hepatocytes with vasopressin evokes increases in cytosolic free Ca2+ ([Ca2+]c) that are relayed into the mitochondria, where the resulting mitochondrial Ca2+ ([Ca2+]m) increase regulates intramitochondrial Ca2+-sensitive targets. To understand how mitochondria integrate the [Ca2+]c signals into a final metabolic response, we stimulated hepatocytes with high vasopressin doses that generate a sustained increase in [Ca2+]c. This elicited a synchronous, single spike of [Ca2+]m and consequent NAD(P)H formation, which could be related to changes in the activity state of pyruvate dehydrogenase (PDH) measured in parallel. The vasopressin-induced [Ca2+]m spike evoked a transient increase in NAD(P)H that persisted longer than the [Ca2+]m increase. In contrast, PDH activity increased biphasically, with an initial rapid phase accompanying the rise in [Ca2+]m, followed by a sustained secondary activation phase associated with a decline in cellular ATP. The decline of NAD(P)H in the face of elevated PDH activity occurred as a result of respiratory chain activation, which was also manifest in a calcium-dependent increase in the membrane potential and pH gradient components of the proton motive force (PMF). This is the first direct demonstration that Ca2+-mobilizing hormones increase the PMF in intact cells. Thus, Ca2+ plays an important role in signal transduction from cytosol to mitochondria, with a single [Ca2+]m spike evoking a complex series of changes to activate mitochondrial oxidative metabolism.
Adenosine Triphosphate↗