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PubMed1995

Neuroligands evoke calcium signaling in cultured myenteric neurons.

BACKGROUND: Myenteric neurons, which control gut motility and absorption, are heterogeneous in structure, electrophysiology, and neuropeptide content. We hypothesized that myenteric neurons would display heterogeneous responses to neuroligands found in enteric tissue. We examined increases in intracellular calcium ([Ca2+]i), an important second messenger, evoked by selected neuroligands in cultured myenteric neurons. METHODS: Primary cultures of guinea pig myenteric neurons were characterized by using a standard immunocytochemical stain for microtubule-associated protein (MAP2). Increases in [Ca2+]i were measured by digital imaging microscopy. Results expressed as mean +/- SEM, Student's t test. RESULTS: Cultured myenteric neurons examined with phase contrast and Nomarsky optics extend processes and stain positively with the neuron-selective stain MAP2. Histamine did not evoke calcium mobilization in cultured neurons, although progressive increases in [Ca2+]i were seen with bradykinin, glutamate, serotonin, cholecystokinin, bombesin, adenosine triphosphate (ATP), substance P, and acetylcholine. Enteric neurons differed from one another in the ability to respond to one, two, or three of the agonist combinations tested. Time in culture did not alter the percentage of neurons responding to ATP, substance P, or acetylcholine. ATP evoked equivalent [Ca2+]i increases in neurons examined at the three time points, whereas significant decrements in neuronal calcium mobilization were seen after 8 days in culture with substance P or acetylcholine (p < 0.05 versus 1 day in vitro). CONCLUSIONS: Cultured myenteric neurons extend processes and retain expression of neuron-specific antigens. Selected neuroligands found in enteric tissue increase [Ca2+]i, as a second messenger in subsets of myenteric neurons. Heterogeneity exists among cultured neurons in their ability to respond to ligand combinations. Changes in [Ca2+]i induced by neuroligands in myenteric neurons may be altered with time in vitro.

Adenosine Triphosphate↗
PubMed2003

Corticosterone enhances adrenocorticotropin-induced calcium signals in bovine adrenocortical cells.

The rapid effects of steroid hormones on Ca(2+) signals have been examined in bovine adrenocortical cells. Among the steroid molecules tested, only corticosterone rapidly stimulated Ca(2+) signals upon addition of ACTH, although corticosterone alone did not induce Ca(2+) signals. Corticosterone also enhanced steroidogenesis induced by ACTH. The enhancement of ACTH-induced Ca(2+) signals was also observed with membrane-impermeable corticosterone conjugated to BSA and was not inhibited by cycloheximide. In addition, corticosterone did not enhance Ca(2+) signals induced by ATP or angiotensin II. These results suggest that corticosterone selectively stimulates ACTH-induced Ca(2+) signals in a nongenomic way by acting on a target in the plasma membrane. Furthermore, the supernatants of cells incubated with ACTH or ATP enhanced Ca(2+) signals, suggesting that steroids produced by such treatment act in an autocrine fashion. Consistent with this idea, these effects were inhibited by inhibitors of steroidogenesis (aminoglutethimide or metyrapone). These results show that steroid molecules synthesized in adrenocortical cells facilitate ACTH-induced Ca(2+) signals. Taken together, corticosterone secreted from adrenocortical cells activates ACTH-induced Ca(2+) signals and steroidogenesis by nongenomic means.

Adrenal Cortex↗
PubMed2006

Calcium signaling in cholangiocytes.

Cytosolic Ca2+ is an important second messenger in virtually every type of cell. Moreover, Ca2+ generally regulates multiple activities within individual cells. This article reviews the cellular machinery that is responsible for Ca2+ signaling in cholangiocytes. In addition, two Ca2+-mediated events in cholangiocytes are discussed: bicarbonate secretion and apoptosis. Finally, emerging evidence is reviewed that Ca2+ signaling is involved in the pathogenesis of diseases affecting the biliary tree and that Ca2+ signaling pathways can be manipulated to therapeutic advantage in the treatment of cholestatic disorders.

Animals↗
PubMed1997

Adherence-dependent calcium signaling in monocytes: induction of a CD14-high phenotype, stimulus-responsive subpopulation.

Isolation of monocytes by plastic adherence alters cell morphology and function. In order to study the effects of cell isolation procedures and subsequent culture on monocyte function, we examined cytoplasmic calcium concentration changes (delta[Ca2+]in) in human monocytes isolated by either negative (magnetic bead) or positive (plastic adherence) selection then stimulated with formyl-Met-Leu-Phe (fMLP), either immediately after isolation, or after 48 h in culture. We have previously shown that fresh adherence-isolated monocytes respond to fMLP with small delta[Ca2+]in and oxidative burst responses, exhibiting larger responses following 48 h of incubation. We now demonstrate that fresh monocytes, prevented from adhering by negative selection, exhibit an even smaller fMLP-induced delta[Ca2+]in, which does not increase during 48 h in culture if cells are kept nonadherent, in Teflon. Calcium responses of adherent, fresh monocytes do not increase if cells are subsequently placed into suspension and maintained nonadherent, but increase if nonadherent cells are permitted to adhere to plastic. Furthermore, augmented fMLP-[Ca2+]in and oxidative burst responses in plastic-adherent cells are restricted to a CD14-high phenotype subpopulation. The CD14-high phenotype also describes a subpopulation of cells that responds to CD4 crosslinking with a rapid delta[Ca2+]in. Induction of a subpopulation of CD14-high expressing cells by adherence may explain in part maturation-induced response changes observed in macrophage but not in monocyte in vitro systems.

CD4 Antigens↗
PubMed1999

Calcium signaling induces acquisition of dendritic cell characteristics in chronic myelogenous leukemia myeloid progenitor cells.

Effective host T lymphocyte sensitization to malignant cells depends on successful antigen presentation. In this study, we examined the capacity of malignant myeloid progenitor cells of patients in the chronic phase of chronic myelogenous leukemia (CML) to acquire characteristics of activated dendritic cells (DCs) after intracellular calcium mobilization, thereby bypassing a need for third-party antigen-presenting cells. Treatment of purified CD33(+) CML cells from 15 patients with calcium ionophore (CI) consistently resulted in de novo expression of the costimulatory molecules CD80 (B7.1) and CD86 (B7.2), CD40 and the DC-specific activation marker CD83, as well as marked up-regulation of MHC class I and II molecules and the adhesion molecule CD54. Most of these changes occurred within 24 hr of treatment. Morphologically, CI-treated CML cells developed long dendritic projections similar to those seen in mature DCs. Functionally, CI-treated CML cells provided stimulation of allogeneic T lymphocytes 10- to 20-fold that of untreated CML cells or untreated monocytes. Fluorescent in situ hybridization of CI-activated CML cells confirmed their leukemic origin by displaying the typical bcr/abl fusion signal. No difference in bcr/abl translocation percentages between untreated and CI-treated CML nuclei was observed. These observations indicate that calcium mobilization may constitute a valuable approach for rapidly and reliably generating CML-derived DCs for immunotherapy of CML.

Antigens, CD↗
PubMed1992

Calcium signalling in single growth hormone-releasing factor-responsive pituitary cells.

The release of pituitary GH appears to be critically dependent on alterations in the free intracellular Ca2+ concentration ([Ca2+]i). However, little is known about the nature of Ca2+ signalling within normal pituitary cells. We, therefore, examined [Ca2+]i patterns in individual cultured pituicytes of adult male rats under basal conditions and in response to GH regulatory agents, using the calcium-sensitive dye fura-2 together with digital imaging microscopy. Perfusion of cultured anterior pituitary cells with GH-releasing factor (GHRF) resulted in a marked increase in [Ca2+]i in specific pituitary cells. These cells did not respond to other hypothalamic secretagogues (GnRH, TRH, or CRF), and there was no evidence of desensitization on repetitive administration of GHRF. Somatotrophs (n = 134) exhibited spontaneous oscillations of [Ca2+]i in the basal state, with considerable heterogeneity of oscillatory patterns among cells. After application of a near-maximal stimulatory dose of GHRF (1 nM), there was a striking 2.2-fold increase in the amplitude of [Ca2+]i oscillations and only a modest increase in their frequency. Forskolin (1 microM) augmented somatotroph [Ca2+]i in patterns similar to those of GHRF. Somatostatin (10 nM) abolished the [Ca2+]i response to GHRF (n = 26); this reflected a marked reduction in the amplitude of [Ca2+]i oscillations and a slight reduction in their frequency. Ca(2+)-free medium or the Ca2+ channel antagonist nimodipine (0.1-1 microM) suppressed the Ca2+ stimulatory effect of GHRF. Conversely, the Ca2+ channel agonist BAY K8644 (1 microM) strikingly augmented the GHRF-induced rise in [Ca2+]i, with a major stimulatory effect on the amplitude of [Ca2+]i oscillations and no observed effect on their frequency. In summary, GHRF and other hypothalamic secretagogues increase [Ca2+]i in pituitary cells in a highly specific manner, consistent with the known specificity of their effects on hormone release. Somatotrophs exhibit spontaneous rhythmic oscillation of [Ca2+]i in the basal state. Known regulators of GH release markedly alter the [Ca2+]i oscillatory pattern in characteristic manners, exerting predominant effects on the amplitude of [Ca2+]i pulses and lesser effects on their frequency. These striking effects of GH regulatory agents on pituitary Ca2+ signalling are consistent with the concept that modulation of [Ca2+]i is a critical mediator of somatotroph function.

Animals↗
PubMed1996

Intra- and intercellular calcium signaling in human neuroepithelioma cells.

The characteristics of intra- and intercellular Ca2+ signaling in human SK-N-MCIXC neuroepithelioma cells have been examined by means of Fura-2 digital imaging microfluorimetry. When cells were exposed to maximally effective concentrations of either endothelin-1, ATP, norepinephrine or oxotremorine-M, the Ca2+ signals that accompany an increase in phosphoinositide turnover could be differentiated on the basis of their magnitude, shape and duration. When individual cells were microinjected with inositol 1,4,5-trisphosphate, a rise in [Ca2+]i was observed not only in the target cell, but also in neighboring cells. This intercellular propagation of Ca2+ signals was found to be mediated via the release of nucleotide di- and triphosphates which subsequently activate purinergic receptors linked to Ca2+ homeostasis on neighboring cells. These results indicate: (1) that agonist-specific Ca2+ 'signatures' are generated in SK-N-MCIXC cells; and (2) that an intercellular propagation of Ca2+ signals is triggered by a rise in [Ca2+]i.

Calcium↗
PubMed1997

An optical method for evaluating ion selectivity for calcium signaling pathways in the cell.

A method for evaluating a physiologically relevant ion selectivity of Ca2+ signaling pathways in biological cells based on a Ca(2+)-dependent on/off switch for cellular processes via calmodulin (CaM) chemistry is described. CaM serves as a primary ion receptor for Ca2+ and a given CaM-binding peptide as a target for a CaM-Ca2+ complex. Upon accommodating four Ca2+ ions in its binding sites, CaM undergoes a conformational change to form a CaM-Ca(2+)-target peptide ternary complex. This Ca(2+)-induced selective binding of the Ca(2+)-CaM complex to the target peptide was monitored by a surface plasmon resonance (SPR) technique. As a target peptide, a 26-amino acid residue of M13 derived from skeletal muscle myosin light-chain kinase was used. The target peptide was covalently immobilized in the dextran matrix on top of gold, over which sample solutions containing Ca2+ and CaM were injected in a flow system. Ca(2+)-dependent SPR signals were observed for Ca2+ concentrations from 3.2 x 10(-8) to 1.1 x 10(-5) M and it leveled off. The observed SPR signals were explained as due to an increase in the refractive indexes caused by a Ca2+ ion-switched protein/ peptide interaction, i.e., Ca2+ ion to CaM and subsequent additional binding of the thus formed complex with immobilized M13. No SPR signals were however, induced by Mg2+, K+, and Li+ at concentrations as high as 1.0 x 10(-1) M; these results and previous spectroscopic data taken together conclude that these ions do not induce CaM/peptide interaction. Large changes in SPR signals were observed with a Sr2+ ion concentration over 5.1 x 10(-4) M; Sr2+ ion behaved in this case as a strong agonist toward the Ca(2+)-dependent on/off switch of CaM. The present system thus exhibited "physiologically more relevant" ion selectivity in that relevant metal ions could switch on the CaM/peptide or -protein interaction rather than merely be bound to CaM causing no further signal transduction. The potential use of this finding for more widely evaluating cation selectivity toward the Ca2+ signaling process was discussed.

Amino Acid Sequence↗
PubMed1991

Distinct structural specificities for functional coupling of the epidermal growth factor receptor to calcium-signalling versus phospholipase A2 responses.

Activation of phospholipase C (PLC), leading to a rise in cytosolic Ca2+, and of phospholipase A2 (PLA2) leading to a release of arachidonic acid, are among the early transmembrane signalling events that have been demonstrated in response to occupancy of the epidermal growth factor (EGF) receptor. The tyrosine kinase activity of the receptor has been shown to be necessary for both of these responses. This requirement for the tyrosine kinase activity could conceivably implicate a role for receptor autophosphorylation in the activation of PLA2. We now demonstrate that coupling of the EGF receptor to PLA2 was not impaired in a deletion mutant (CD126) devoid of the 126 amino acids from the C-terminus which include four major autophosphorylation sites. Functional coupling of the EGF receptor to PLA2 was demonstrated using three different experimental designs: (1) release of [14C]arachidonic acid from prelabelled intact cells. (2) release of [3H]arachidonic acid from prelabelled cells permeabilized with glass beads, and (3) direct measurement of PLA2 enzymic activity in cell-free extracts using an 'in vitro' assay employing exogenous phospholipid substrate. Functional coupling of the EGF receptor to PLA2 occurred despite the absence of a demonstrable Ca(2+)-signalling response and the detection of diminished but persistent PLC-gamma phosphorylation on tyrosine residues in the CD126 deletion mutants. These results point to a clear distinction in the biochemical mechanism and role for receptor autophosphorylation in functional coupling of the EGF receptor to PLA2 activation versus Ca2+ signalling.

Arachidonic Acid↗
PubMed1995

Calcium signal prolongation in sensory neurones of mice with experimental diabetes.

Depolarization-induced Ca2+ transients were studied in dorsal root ganglion neurones of different size (large, 30-45 microns; small, 18-25 microns in diameter) from normal and diabetic mice. Whereas in large neurones no definite changes in the amplitude and time course of the transients were observed, in small neurones the decay of transient became substantially prolonged during streptozotocin-induced and spontaneously occurring diabetes. As small and large neurones differ substantially in their mechanisms of Ca2+ transient termination, we conclude that the prolongation of Ca2+ transients, probably induced by chronic hyperglycaemia, is specific only for small sensory neurones (transmitting mostly nociceptive signals) and may be a cause of the increased pain sensitivity often accompanying this disease.

Animals↗
PubMed1995

Calcium signaling in a narrow somatic submembrane shell during synaptic activity in cerebellar Purkinje neurons.

Temporal and spatial changes in the intracellular Ca2+ concentration ([Ca2+]i) were examined in dendrites and somata of rat cerebellar Purkinje neurons by combining whole-cell patch-clamp recording and fast confocal laser-scanning microscopy. In cells loaded via the patch pipette with the high-affinity Ca2+ indicator Calcium Green-1 (Kd approximately 220 nM), a single synaptic climbing fiber response, a so-called complex spike, resulted in a transient elevation of [Ca2+]i that showed distinct differences among various subcellular compartments. With conventional imaging, the Ca2+ signals were prominent in the dendrites and almost absent in the soma. Confocal recordings from the somatic region, however, revealed steep transient increases in [Ca2+]i that were confined to a submembrane shell of 2- to 3-microns thickness. In the central parts of the soma [Ca2+]i increases were much slower and had smaller amplitudes. The kinetics and amplitudes of the changes in [Ca2+]i were analyzed in more detail by using the fast, low-affinity Ca2+ indicator Calcium Green-5N (Kd approximately 17 microM). We found that brief depolarizing pulses produced [Ca2+]i increases in a narrow somatic submembrane shell that resembled those seen in the dendrites. These results provide direct experimental evidence that the surface-to-volume ratio is a critical determinant of the spatiotemporal pattern of Ca2+ signals evoked by synaptic activity in neurons.

Animals↗
PubMed1995

S-phase independence of parathyroid hormone-induced calcium signalling in primary osteoblast-like cells.

Cell cycle-dependence of parathyroid hormone (PTH)-induced signal transduction was studied at the single cell level in fetal rat osteoblast-like cells (ROB) in primary culture. Responsiveness to 10(-7) M rPTH1-34 was measured as changes in the intracellular calcium concentration ([Ca2+]i) of cells loaded with Fura-2 using a video imaging setup. Cells in S-phase were identified by staining for incorporated 5-bromo-2'-deoxyuridine (BrdU). ROB were cultured on glass coverslips which had alphanumerically marked gratings so that cells could be located. Directly after measurement of the PTH-induced [Ca2+]i response of the individual cells, cells were fixed and stained for incorporated BrdU. Phase-contrast images taken with the video imaging setup were compared with phase-contrast micrographs and fluoro-micrographs taken after staining for BrdU incorporation. We found that 43% of the cells responding to PTH with a rise in [Ca2+]i had also incorporated BrdU. This percentage was not different from the percentage BrdU positive cells in the whole culture, showing that calcium responsiveness was randomly distributed between ROB in S-phase and those not in S-phase. We therefore conclude that PTH does not induce calcium responses preferentially during the S-phase of the cell cycle in ROB in primary culture.

Animals↗
PubMed1981

Phosphatidylinositol hydrolysis and calcium signaling.

The salivary glands of the blowfly possess two separate 5-HT receptors. One receptor system is linked to adenylate cyclase to produce cyclic AMP, which regulates cation transport across the epithelium. The other receptor acts through calcium, which stimulates anion transport. Activation of this second receptor is associated with the specific hydrolysis of phosphatidylinositol (PI) to give a PI response that appears to be a characteristic feature of receptors that act through calcium. Studies on this insect gland have established a close correlation between PI hydrolysis and changes in calcium gating. The idea that these two receptor-mediated events might be intimately related was strengthened by the observation that the ability of 5-HT to gate calcium could be varied by adjusting the level of PI in the membrane.

Animals↗
PubMed1994

Cellular and subcellular calcium signaling in gastrointestinal epithelium.

Ca2+ is a critical second messenger in virtually all cell types, including the various epithelial cell types within the digestive system. When measured in cell populations, Ca2+ signals usually appear as a single transient or prolonged elevation. In individual epithelial cells, signaling patterns often vary from cell to cell and may contain more complex features such as Ca2+ oscillations. Subcellular Ca2+ signals show a further level of complexity, such as Ca2+ waves, and may relate to the polarized structure and function of epithelial cells. The approaches to detect cytosolic Ca2+ signals, the patterns and mechanisms of Ca2+ signaling, and the role of such signals in regulating the function of polarized epithelium within the gastrointestinal tract, pancreas, and liver are reviewed in this report.

Calcium↗
PubMed1996

Modulator and messenger functions of cyclic ADP-ribose in calcium signaling.

Cyclic ADP-ribose (cADPR), a Ca+2 mobilizing cyclic nucleotide derived from NAD+, is emerging as an endogenous modulator of the Ca(+2)-induced Ca+2 release (CICR) mechanism in cells. cADPR was discovered because of the prominent delay in the initiation of Ca+2 release by NAD+ in sea urchin egg homogenates, which was due to enzymatic conversion to cADPR. In addition to the egg, an invertebrate cell, amphibian neurons, a variety of mammalian cells and plant vacuoles are found to be responsive to cADPR, indicating its generality. The cyclic structure of cADPR has been determined by X-ray crystallography. A series of analogs has been synthesized, which includes cyclic GDP-ribose, a fluorescent analog, a series of specific antagonists, a photoaffinity label and caged cADPR. The use of these analogs of cADPR has provided definitive evidence for the authenticity of its Ca+2 mobilizing activity and insights for understanding its mechanism and biological functions. Results show that its action requires a soluble protein which is identified as calmodulin. The effect of calmodulin is synergistic with cADPR and both act to sensitize CICR to Ca+2. Together, the Ca+2 sensitivity of CICR can be increased by several orders of magnitude. In addition to being a modulator of CICR. cADPR can also function as a messenger. Activation of its synthetic enzyme can lead to large increases in cellular concentrations of cADPR, which would sensitize CICR to such an extent that even basal levels of cellular Ca+2 are sufficient to trigger further release. This is operationally equivalent to being a Ca+2 messenger. Three types of enzymes are involved in the metabolism of cADPR, a soluble ADP-ribosyl cyclase; a bifunctional ecto-enzyme, CD38, which is also a lymphocyte antigen; and an intracellular enzyme activable by a cGMP-dependent process. The importance of two cysteine residues in the bifunctionality of CD38 has been shown by site-directed mutagenesis. Both ADP-ribosyl cyclase and CD38 can catalyze the exchange of the nicotinamide group in NADP+ with nicotinic acid, leading to the formation of another Ca+2 mobilizing metabolite, nicotinic acid dinucleotide phosphate (NAADP). Pharmacological and desensitization studies show that the NAADP-mechanism is totally independent of the cADPR- and inositol trisphosphate-mechanisms and the Ca+2 stores responsive to NAADP are separable from those sensitive to the other two Ca+2 agonists. Microinjection studies show that all three mechanisms are present and functional in cells. The emerging picture of multiplicity in Ca+2 signaling mechanisms underscores the versatility of Ca+2 in regulating diverse cellular functions.

Adenosine Diphosphate Ribose↗
PubMed1995

Calcium signaling in single rat Leydig cells.

The steroidogenic activity of the Leydig cell is regulated by glycoprotein and peptide hormones with the potential to activate both adenylate cyclase and phospholipase C. Although the control of androgen production by LH is clearly mediated by cAMP, the extent to which Ca(2+)-mobilizing stimuli control Leydig cell function is less well defined. The basal level of intracellular calcium ([Ca2+]i) in adult rat Leydig cells was 70-160 nM and was unaffected by high K+ or the dihydropyridine calcium channel agonist, Bay K 8644. These findings are consistent with the absence of voltage-sensitive calcium channels in the Leydig cell. In addition, no increase in [Ca2+]i was observed in cells treated with LH, CRF, and serotonin. However, both GnRH and endothelin-1 (ET-1) induced rapid and transient elevations of [Ca2+]i that were not associated with a sustained plateau phase and were unaffected by removal of Ca2+ from the incubation medium. The amplitude of the [Ca2+]i response was not altered by increasing concentrations of GnRH and ET-1, but the number of responsive cells increased progressively to a maximum of about 30% of the Leydig cell population. The calcium-mobilizing actions of GnRH and ET-1 were abolished by the GnRH and ETA receptor antagonists, [Dp-Glu1,D-Phe2,D- Trp3,6]GnRH and BQ-123, respectively. The majority of the cells expressed solely GnRH or ETA receptors, and about 10% expressed both receptors. GnRH-induced Ca2+ responses were observed almost exclusively in medium-sized Leydig cells, whereas ET-induced responses were most frequent in large Leydig cells. These data demonstrate that single Leydig cells expressing GnRH and ETA receptors exhibit monophasic [Ca2+]i responses that are activated in an all-or-none fashion. Such transient Ca2+ signaling may trigger short term cellular responses or could modulate the actions of gonadotropins acting through the cAMP signaling pathway.

Animals↗