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At least 1,189 records · Page 66Linked to original sources
PubMed1993

Metabotropic glutamate receptors and calcium signalling in dendrites of hippocampal CA1 neurones.

We have combined patch-clamp recording with confocal microscopy to investigate how the synaptic activation of metabotropic glutamate receptors (mGluRs) may participate in the modulation of intracellular free calcium (Ca2+) in the dendrites of single CA1 pyramidal neurones, within hippocampal slices. Tetanic stimulation (100 Hz, 1 sec) of the Schaffer collateral-commissural pathway led to a transient rise in Ca2+ in the dendrites of neurones voltage- clamped at -35 mV, as determined using the fluorescent indicator fluo-3. The specific mGluR antagonist (+)-alpha-methyl-4-carboxyphenylglycine (MCPG), applied at a concentration of 250 or 500 microM, reduced the size of the Ca2+ transient whilst either producing a small reduction or, more commonly, having no effect on the synaptic current evoked by the tetanus. These data suggest that the synaptic activation of mGluRs can contribute to Ca2+ signalling in hippocampal neurones.

2-Amino-5-phosphonovalerate↗
PubMed2000

Nuclear calcium signalling.

The topic of nuclear Ca2+ signalling is beset by discrepant observations of substantial nuclear/cytoplasmic gradients. The reasons why some labs have recorded such gradients, whilst other workers see equilibration of Ca2+(cyt) and Ca2+(nuc) using the same cells and techniques, is unexplained. Furthermore, how such gradients could arise across the NE that possesses many highly-conductive NPCs is a mystery. Although nuclei may have the capacity to be autonomous signalling entities, with functional Ca2+ release channels and an inositide cycle, the balance of evidence suggests that Ca2+ release on the inner NE does not occur during physiological stimulation. Our work suggests that elementary Ca2+ release events originating in the cytoplasm can give rise to Ca2+ signals without causing elevation of the bulk cytoplasm. Clearly, the many Ca2+ signalling mechanisms that may impinge on Ca2+(nuc) will remain a topic of controversy and debate for some time.

Animals↗
PubMed1998

The regulation of gonadotropin-releasing hormone-induced calcium signals in male rat gonadotrophs by testosterone is mediated by dihydrotestosterone.

The biological effects of testosterone (T) may be mediated directly by T or indirectly by its metabolites, dihydrotestosterone (DHT) and estradiol. The present study examined whether the metabolism of T is involved in the regulation of GnRH-induced Ca2+ signaling at the pituitary. In gonadotrophs from castrated rats, a significantly greater percentage of gonadotrophs demonstrated oscillatory Ca2+ responses to 100 nM GnRH than cells from intact rats (72% vs. 24%; P < 0.05). This increase was prevented by the administration of T propionate (0.1 mg/kg x day), DHT benzoate (2 mg/kg x day,), estradiol benzoate (EB; 5 microg/kg x day), or the combination of the above doses of DHT benzoate and EB. In all cases the proportion of gonadotrophs from the steroid-treated rats having oscillatory Ca2+ responses to 100 nM GnRH was between 21-25% (P > 0.05, compared with intact rats). To assess the importance of T metabolism, intact male rats were treated with the aromatase inhibitor letrozole (1 mg/kg x day), the 5alpha-reductase inhibitor finasteride (50 mg/kg x day), or their respective vehicles for 7 days. Letrozole had no effect on GnRH-induced Ca2+ signals, serum LH concentrations, or ventral prostate or testes weight. Finasteride treatment, however, mimicked the effects of castration, with significantly more gonadotrophs exhibiting Ca2+ oscillations in response to 100 nM GnRH than gonadotrophs from the vehicle-treated group (71% vs. 20% respectively; P < 0.05). Finasteride also caused a significant (P < 0.05) decrease in prostatic weight and DHT concentration, but had no significant effect on either prostatic T or serum LH concentrations. These findings suggest that in the intact male rat, the effects of T on GnRH-induced Ca2+ signaling are preferentially mediated via DHT. The results of this study also show that in the absence of androgens, estradiol may regulate GnRH-induced Ca2+ signaling in the male rat pituitary.

Animals↗
PubMed1993

Ketamine inhibition of cytoplasmic calcium signalling in rat pheochromocytoma (PC-12) cells.

This study examines the mechanism of action of ketamine, a dissociative anesthetic, with a specific focus on its ability to inhibit changes in the concentration of intracellular free calcium, [Ca2+]i, in PC-12 cells. The resting [Ca2+]i as measured with the fluorescent probe Fura-2 AM in control cells is 184.8 +/- 8.6 nM (mean +/- SEM, n = 15). Changes in [Ca2+]i via influx through voltage-gated calcium channels after membrane depolarization with potassium chloride were monitored in the absence and presence of various concentrations of ketamine. Potassium-depolarization caused a dose-dependent rapid increase in [Ca2+]i, averaging 62 +/- 5%, 33 +/- 2% and 18 +/- 3% (n = 10 each) above control levels for 70 mM, 50 mM and 35 mM KCl, respectively. Ketamine, in the dosage range studied (5-500 microM), inhibited the increase in [Ca2+]i stimulated by potassium-depolarization in a dose-dependent manner. The computer-fitted dose-response curve of the pooled data yielded a half maximal suppression concentration, ED50, of 33 microM. In conclusion, this study demonstrates that ketamine inhibits Ca2+ influx through voltage-gated Ca2+ channels in PC-12 cells at clinically relevant doses, and may play a role in ketamine's action as a general anesthetic agent.

Animals↗
PubMed1995

Potentiation by tumour necrosis factor-alpha of calcium signals induced by bradykinin and carbachol in human tracheal smooth muscle cells.

The effect of tumour necrosis factor-alpha (TNF alpha) on the increase in cytosolic free calcium ([Ca2+])i induced by carbachol and bradykinin (BK) was investigated in human tracheal smooth muscle cells in culture (TSMC). BK (10(-12)-10(-9) M) and carbachol (10(-7)-10(-3) M) produced a concentration-dependent increase in [Ca2+]i (pD2 = 10.73 +/- 0.05 and 5.57 +/- 0.03 respectively). The increase in [Ca2+]i was significantly enhanced for both agonists in TNF alpha-treated cells (10 ng ml-1 for 24 h). However, pD2 values were not modified (10.78 +/- 0.03 and 5.62 +/- 0.04 for BK and carbachol, respectively) suggesting that no change in the apparent receptor affinity occurred. Thus, TNF alpha induced-alterations in Ca2+ homeostasis in human TSMC may be a key mechanism underlying airway hyperreactivity.

Bradykinin↗
PubMed1996

Calcium storage and release properties of F-actin: evidence for the involvement of F-actin in cellular calcium signaling.

Preceding studies have shown that the bulk of the ATP-dependent, inositol 1,4,5-trisphosphate (IP3)-sensitive Ca2+ store of hamster insulinoma (HIT) cells is located in microvilli on the cell surface. Similar results were obtained with isolated rat hepatocytes. Moreover, in vesicles of microvillar origin, passive fluxes of Ca2+, ATP, and IP3 occur through cation and anion channels, respectively, suggesting that Ca2+ storage is due to ATP-dependent Ca2+ binding to an intravesicular component. Here we demonstrate that F-actin may be a possible candidate for this function. ATP-actin monomers bind Ca2+ with high affinity (Kd = 2-8 nM) to their divalent cation binding sites. Polymerization of actin monomers decreases the rate constant for divalent cation exchange at this binding site by more than 3 orders of magnitude rendering bound cations nearly unavailable. F-actin-bound Ca2+ can be released by depolymerization and dissociation from Ca(2+)-ADP-actin monomers (Kd = 375 nM). We now provide additional evidence for the possible involvement of actin in Ca2+ storage. (1) Preincubation of surface-derived Ca(2+)-storing vesicles from HIT cells with the F-actin stabilizer, phalloidin, strongly inhibited ATP-dependent Ca2+ uptake, reducing the IP3-sensitive Ca2+ pool by 70%. Phalloidin, when added after the loading process, affected neither the amount of stored Ca2+ nor IP3 action on the store. (2) F-actin polymerized in the presence of Mg2+ in nominally Ca(2+)-free buffer still contained about half of the high affinity sites occupied with Ca2+ (Mg/Ca-F-actin). (3) Using the fura-2 technique, we found that in the presence of ATP, Mg/Ca-F-actin incorporated free Ca2+ at a relatively low rate. Short pulses of ultrasound (3-10 s) strongly accelerated Ca2+ uptake, decreasing free Ca2+ from 500 nM to below 100 nM. (4) In the presence of physiological levels of Mg2+ (0.5 mM), sonication liberated large amounts of Ca2+ from Mg/Ca-F-actin. (5) Ca-F-actin released bound Ca2+ at a very slow rate. Short ultrasonic pulses rapidly elevated free Ca2+ from about 50 nM up to 500 nM. (6) Small amounts of profilin, an actin-binding protein, released Ca2+ both from Ca- and Mg/Ca-F-actin and also inhibited uptake of Ca2+ into Mg/Ca-F-actin. (7) Phalloidin completely inhibited Ca-uptake into Mg/Ca-F-actin even during ultrasonic treatment. These findings suggest that Ca2+ storage may occur by addition of Ca-ATP-actin monomers to reactive ends of the polymer and emptying of this store by profilin-stimulated release of Ca-ADP-actin. Thus, receptor-operated Ca2+ signaling, initiated by phospholipase C activation, may proceed via the well-known phosphatidylinositol phosphate-regulated profilin/gelsolin pathway of actin reorganization/depolymerization. The importance of the proposed microvillar Ca2+ signaling system for living cells remains to be established.

Actins↗
PubMed1996

Calcium signaling restitution prevents T-cell proliferative suppression by prostaglandin E2.

Previous studies from our laboratory have implicated a role for Ca2+ in prostaglandin E2 (PGE2)-induced suppression in T-cell proliferation during sepsis. The present study further elucidated the mechanism of PGE2-induced suppression in T-cell proliferation. We assessed whether prevention of the suppression in Ca2+ mobilization in PGE2-treated T-cells would restore proliferation. Rat splenic T-cell Ca2+ mobilization and proliferation were measured after stimulation of cells with concanavalin A (Con A) employing Fura-2 spectroscopy and cellular [3H]thymidine uptake techniques, respectively. PGE2 and other agents that directly up-regulate the PGE2-mediated cell signaling events (e.g., cholera toxin and forskolin), substantially suppressed both Con A-induced proliferation (p < .01) and Ca2+ mobilization in T-cells (p < .01). When stimulated with Con A plus ionomycin, [Ca2+]i in PGE2 treated T-cells (395 +/- 21, nM) was not significantly different (p > .05) from that observed in Con A-stimulated T-cells without the PGE2 exposure (351 +/- 8.6). The stimulation of PGE2-treated T-cells with ionomycin and Con A also significantly (p < .025), if not completely, prevented the PGE2-induced suppression in T-cell proliferation. These results suggest that the cross-talk between the TCR- and PGE2-mediated signaling in T-cells negatively modulates the TCR signals at the Ca2+ mobilization step and/or earlier to it.

Animals↗
PubMed1992

Modulation of cytoplasmic calcium signaling in rat pituitary gonadotrophs by estradiol and progesterone.

The stimulatory action of GnRH on gonadotropin secretion from cultured rat pituitary cells is modulated by estradiol (E) and progesterone (P). Since secretory responses to GnRH are initiated by phosphoinositide hydrolysis and Ca2+ mobilization, the effects of gonadal steroids on the pattern of Ca2+ signaling were analyzed in single pituitary gonadotrophs. Increasing concentrations of GnRH elicited a spectrum of [Ca2+]i signals in single gonadotrophs, ranging from subthreshold to threshold-oscillatory and biphasic (spike & plateau) responses. In E-treated gonadotrophs, short-term P treatment shifted subthreshold [Ca2+]i responses to oscillatory and oscillatory to biphasic responses, whereas long-term P treatment shifted oscillatory to subthreshold [Ca2+]i response profiles. These changes parallel the effects of P on GnRH-induced LH release, and indicate that the modulatory effects of ovarian steroids on gonadotropin secretion include a significant action on the Ca2+ signaling pathway.

Animals↗
PubMed1998

Nucleotide-evoked calcium signals and anion secretion in equine cultured epithelia that express apical P2Y2 receptors and pyrimidine nucleotide receptors.

1. Experiments with a spontaneously transformed equine epithelial cell line showed that certain nucleotides increased intracellular free calcium ([Ca2+]i) in cells plated on glass coverslips. The rank order of potency was ATP UTP > 5-Br-UTP, whilst UDP and ADP were ineffective. The response thus appears to be mediated by P2Y2 receptors. 2. Nucleotides also increased short circuit current (Isc) in cells grown into epithelial monolayers and the rank order of potency was UDP> UTP > 5-Br-UTP > ATP > ADP. The increase in [Ca2+]i and the rise in ISC thus have different pharmacological properties. Cross-desensitization experiments indicated that, as well as P2Y2 receptors, the monolayer cultures express at least one additional receptor population that allowed nucleotides to increase ISC. 3. The UDP-evoked increase in ISC was essentially abolished in BAPTA-loaded epithelia suggesting that this response is dependent upon increased [Ca2+]i. Moreover, experiments in which ISC and [Ca2+]i were measured simultaneously showed that the UDP- and ADP-evoked increases in ISC were accompanied by increases in [Ca2+]i. 4. When grown under conditions which favour the development of a polarized phenotype, these epithelial cells thus appear to express [Ca2+]i-mobilizing receptors sensitive to UDP and ADP that are not present in non-polarized cells on coverslips.

Adenosine Diphosphate↗
PubMed1998

Inhibitory action of mibefradil on calcium signaling and aldosterone synthesis in bovine adrenal glomerulosa cells.

Mibefradil is a new cardiovascular drug with peculiar Ca++ antagonistic properties. The most remarkable feature of mibefradil is its unique relative selectivity for T type calcium channels, a property that has been proposed to explain in part the beneficial pharmacological and clinical profiles of this drug. In adrenal glomerulosa cells, aldosterone biosynthesis and secretion in response to angiotensin II or extracellular potassium is dependent on a sustained influx of Ca++ through T type Ca++ channels. The effect of mibefradil on the steroidogenic function of glomerulosa cells was therefore investigated. Using the patch clamp technique, we found that mibefradil inhibits selectively and in a concentration-dependent manner (IC50 = 3 microM)++ T type currents in bovine glomerulosa cells. In addition to this tonic (voltage independent) inhibition, the drug also induced a shift of the steady-state inactivation curve of these channels toward hyperpolarized voltages, contributing to its efficacy to prevent Ca++ influx into the cell through T type channels. Concomitantly, mibefradil reduced the cytosolic calcium responses to potassium and angiotensin II (as assessed with fluorescent probes), without affecting the capacitative Ca++ influx, and inhibited pregnenolone and aldosterone formation. This inhibition of steroidogenesis was not exclusively due to mibefradil action on voltage-operated Ca++ channels, because this agent also partially reduced steroid synthesis induced by adrenocorticotropic hormone or forskolin, two activators of the cyclic AMP pathway. In conclusion, mibefradil is highly effective in adrenal glomerulosa cells in reducing T type channel activity and aldosterone biosynthesis, two actions that should contribute to the beneficial effect of the drug in the treatment of hypertension.

Aldosterone↗
PubMed1993

Ultraviolet radiation induces differential calcium signals in human peripheral blood lymphocyte subsets.

Ultraviolet (UV) irradiation is known to suppress normal lymphocyte function, which allows UV phototherapy for a variety of applications. Although UV radiation is well known to cause DNA damage, recent findings indicate that UV irradiation can activate cellular signal-transduction processes. We have previously found that UV induces tyrosine phosphorylation in lymphocytes in a dose- and wavelength-dependent manner and also induces Ca2+ signals in Jurkat T cells via tyrosine phosphorylation of PLC gamma 1 and associated proteins. In this study, normal human lymphocyte subsets were examined for UV-induced Ca2+ responses. CD4+ and CD8+ T cells gave strong responses, whereas other cells did not. Although B cells did not have substantial Ca2+ signals, the pattern of UV-induced tyrosine phosphorylation was very similar to that observed after surface immunoglobulin cross-linking. We propose that the inhibitory effect of UV on lymphocyte function may be due in part to an active induction of tyrosine phosphorylation and Ca2+ signals by a process that bypasses normal receptor control.

CD4-Positive T-Lymphocytes↗
PubMed1995

The amplifying effect of beta-amyloid on cellular calcium signalling is reduced in Alzheimer's disease.

The amplifying effect of beta-amyloid fragment 25-35 (beta A25-35) on the mitogen-induced rise of free intracellular calcium in circulating lymphocytes was strongly reduced in 24 patients with Alzheimer's disease when compared with elderly, non-demented controls. Low beta-amyloid responses were significantly correlated with the presence of the apolipoprotein E epsilon 4 allele, suggesting a dose effect.

Adult↗