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PubMed1990

Calcium, calcium channels, and calcium channel antagonists.

Voltage-dependent Ca2+ channels are an important pathway for Ca2+ influx in excitable cells. They also represent an important site of action for a therapeutic group of agents, the Ca2+ channel antagonists. These drugs enjoy considerable use in the cardiovascular area including angina, some arrhythmias, hypertension, and peripheral vascular disorders. The voltage-dependent Ca2+ channels exist in a number of subclasses characterized by electrophysiologic, permeation, and pharmacologic criteria. The Ca2+ channel antagonists, including verapamil, nifedipine, and diltiazem, serve to characterize the L channel class. This channel class has been characterized as a pharmacologic receptor, since it possesses specific drug-binding sites for both antagonists and activators and it is regulated by homologous and heterologous influences. The Ca2+ channels of both voltage- and ligand-regulated classes are likely to continue to be major research targets for new drug design and action.

Animals↗
PubMed2001

Calcium puffs are generic InsP(3)-activated elementary calcium signals and are downregulated by prolonged hormonal stimulation to inhibit cellular calcium responses.

Elementary Ca(2+) signals, such as "Ca(2+) puffs", which arise from the activation of inositol 1,4,5-trisphosphate receptors, are building blocks for local and global Ca(2+) signalling. We characterized Ca(2+) puffs in six cell types that expressed differing ratios of the three inositol 1,4,5-trisphosphate receptor isoforms. The amplitudes, spatial spreads and kinetics of the events were similar in each of the cell types. The resemblance of Ca(2+) puffs in these cell types suggests that they are a generic elementary Ca(2+) signal and, furthermore, that the different inositol 1,4,5-trisphosphate isoforms are functionally redundant at the level of subcellular Ca(2+) signalling. Hormonal stimulation of SH-SY5Y neuroblastoma cells and HeLa cells for several hours downregulated inositol 1,4,5-trisphosphate expression and concomitantly altered the properties of the Ca(2+) puffs. The amplitude and duration of Ca(2+) puffs were substantially reduced. In addition, the number of Ca(2+) puff sites active during the onset of a Ca(2+) wave declined. The consequence of the changes in Ca(2+) puff properties was that cells displayed a lower propensity to trigger regenerative Ca(2+) waves. Therefore, Ca(2+) puffs underlie inositol 1,4,5-trisphosphate signalling in diverse cell types and are focal points for regulation of cellular responses.

Adenosine Triphosphate↗
PubMed1997

Outward potassium current oscillations in macrophage polykaryons: extracellular calcium entry and calcium-induced calcium release.

Outward current oscillations associated with transient membrane hyperpolarizations were induced in murine macrophage polykaryons by membrane depolarization in the absence of external Na+. Oscillations corresponded to a cyclic activation of Ca(2+)-dependent K+ currents (IKCa) probably correlated with variations in intracellular Ca2+ concentration. Addition of external Na+ (8 mM) immediately abolished the outward current oscillations, suggesting that the absence of the cation is necessary not only for their induction but also for their maintenance. Oscillations were completely blocked by nisoldipine. Ruthenium red and ryanodine reduced the number of outward current cycles in each episode, whereas quercetin prolonged the hyperpolarization 2- to 15-fold. Neither low molecular weight heparin nor the absence of a Na+ gradient across the membrane had any influence on oscillations. The evidence suggests that Ca2+ entry through a pathway sensitive to Ca2+ channel blockers is elicited by membrane depolarization in Na(+)-free medium and is essential to initiate oscillations, which are also dependent on the cyclic release of Ca2+ from intracellular Ca(2+)-sensitive stores; Ca2+ ATPase acts by reducing intracellular Ca2+, thus allowing slow deactivation of IKCa. Evidence is presented that neither a Na+/Ca2+ antiporter nor Ca2+ release from IP3-sensitive Ca2+ stores participate directly in the mechanism of oscillation.

Animals↗
PubMed2003

A calcium-induced calcium influx factor, nitric oxide, modulates the refilling of calcium stores in astrocytes.

The roles of nitric oxide are primarily undefined in astrocytes, cells that are active partners in synaptic transmission. Because nitric oxide synthases are present in astrocytes, we imaged the formation of nitric oxide in cultured murine cortical astrocytes using DAF-FM (4-amino-5-methylamino-2',7'-difluorofluorescein diacetate). We demonstrated that physiological concentrations of ATP induced a Ca2+-dependent production of nitric oxide. We then investigated the roles of nitric oxide in astrocytic Ca2+ signaling by exogenous application of a nitric oxide donor and found that nitric oxide induced an influx of external Ca2+. Because these observations raise the possibility that nitric oxide-dependent Ca2+ influx could lead to the refilling of internal stores with Ca2+, we directly monitored the Ca2+ levels of the cytosol and of internal stores while manipulating nitric oxide. Cultures were coloaded with mag-fluo-4 and X-rhod-1 to differentially load the internal stores and cytosol, respectively. ATP induced a cytosolic increase in Ca2+ that results from the IP3-dependent release of Ca2+ from internal stores, detected as a simultaneous reduction in mag-fluo-4 and an increase in X-rhod-1 fluorescence. To monitor store refilling, we measured the recovery of mag-fluo-4 fluorescence after removal of ATP. When nitric oxide signaling was blocked by the nitric oxide scavenger 2-phenyl-4,4,5,5-ketramethyl-imidazoline-1-oxyl-3-oxide or by the nitric oxide synthase inhibitor NG-monomethyl-l-arginine, fluorescence recovery was significantly reduced. These data suggest that transmitters that induce Ca2+ signaling in astrocytes lead to the Ca2+-dependent synthesis of nitric oxide. This in turn stimulates a Ca2+ influx pathway that is, in part, responsible for the refilling of internal Ca2+ stores.

Adenosine Triphosphate↗
PubMed2005

Calcium transport in human salivary glands: a proposed model of calcium secretion into saliva.

Salivary calcium plays a vital role in bio-mineralization of dental enamel and exposed dentin. In order to elucidate the yet unknown cellular and molecular mechanisms of calcium secretion in human salivary glands the presence of various relevant plasma membrane transport systems for calcium were investigated. Using an RT-PCR approach, expression of the epithelial calcium channel (CaT-Like), the calcium binding protein (calbindin-2), the endoplasmic reticulum pumps (SERCA-2 and -3), and the plasma membrane calcium ATPases (PMCA-1, -2, and -4), were found in parotid and submandibular glands. Immunohistochemistry revealed that CaT-Like is located in the basolateral plasma membrane of acinar cells; while calbindin-2, SERCA-2 and SERCA-3 were found inside the acinar cells; and PMCA-2 was found in the apical membrane and in the secretory canaliculi between the cells. Based on these findings, we propose the following model of calcium secretion in human salivary glands: (1) calcium enters the acinar cell at the basolateral side via calcium channel CaT-Like (calcium influx); (2) intracellular calcium is taken up into the endoplasmic reticulum by SERCA-2 and possibly SERCA3 or bound to calbindin-2 (intracellular calcium pool); and (3) calcium is secreted by PMCAs at the apical plasma membrane (calcium efflux).

Adult↗
PubMed1990

Calcium exchange in rabbit myocardium during and after hypoxia: role of sodium-calcium exchange.

Calcium uptake was measured using 47Ca2+ in the isolated and arterially perfused interventricular septum of the rabbit. Experiments were undertaken to determine whether calcium uptake on reoxygenation is linked to recovery of mechanical function and whether calcium uptake is through the sodium-calcium exchange mechanism. During substrate-free hypoxia for 45 min total tissue calcium remained unchanged but immediately upon reoxygenation there was a substantial net gain of calcium. Recovery of mechanical function upon reoxygenation was inversely related to the increase in tissue calcium. Activation of sodium-calcium exchange by perfusion with a low-sodium, zero-potassium, sucrose solution also increased tissue calcium and the relation to mechanical recovery was similar to that observed on reoxygenation. The sodium-calcium exchange mechanism was not affected by hypoxia and could be demonstrated during perfusion with a substrate-free hypoxic solution. Lithium (100 mM) substitution for sucrose prevented the calcium influx induced by a low-sodium and zero-potassium perfusate under normoxic conditions. Lithium substitution early during hypoxia or on reoxygenation did not affect the increase in myocardial calcium on reoxygenation. Amiloride (10(-4)M), presumed to inhibit sodium-hydrogen exchange during hypoxia, had no effect upon reoxygenation induced calcium uptake. It is concluded that the increase in calcium uptake that occurs on reoxygenation after a period of substrate-free hypoxia is related to mechanical recovery. Sodium-calcium exchange may contribute to calcium uptake on reoxygenation in this experimental model but is not the major mechanism.

Amiloride↗
PubMed1992

Calcium mass transfer with dialysate containing 1.25 and 1.75 mmol/L calcium in peritoneal dialysis patients.

Studies with 1.75 mmol/L calcium dialysate have shown that patients gain calcium from dialysate. Thus, hypercalcemia, especially when calcium compounds are used for phosphate control, is a commonly seen complication. Dialysate with 1.25 mmol/L calcium has been available since 1989. Little is known about calcium mass transfer (CMT) with dialysate of this calcium concentration. CMT was measured in 20 stable adult peritoneal dialysis patients. Each CMT study consisted of a 2-L continuous ambulatory peritoneal dialysis (CAPD) exchange with a dwell time of 4 hours. CMT studies were performed using 1.25 and 1.75 mmol/L calcium dialysate with 1.5, 2.5, and 4.25 g/dL dextrose concentrations. CMT with 1.25 mmol/L calcium dialysate was compared to that with 1.75 mmol/L for each dextrose concentration. With a dextrose concentration of 1.5 g/dL, the mean CMT for 1.25 mmol/L calcium dialysate was -0.1 +/- 0.3 mmol versus 0.6 +/- 0.3 mmol for 1.75 mmol/L calcium dialysate (P < 0.0001). A dextrose concentration of 2.5 g/dL resulted in a mean CMT of -0.4 +/- 0.2 mmol for 1.25 mmol/L calcium versus 0.45 +/- 0.25 mmol for 1.75 mmol/L calcium (P < 0.0001). Using a dextrose concentration of 4.25 g/dL, the mean CMT was -0.7 +/- 0.25 mmol for 1.25 mmol/L calcium versus -0.05 +/- 0.35 mmol for 1.75 mmol/L calcium (P < 0.0001). Mean serum ionized calcium (SiCa) was between 1.15 and 1.20 mmol/L for all study groups. CMT inversely correlated with SiCa for each type of dialysate used. CMT was dependent on the concentrations of calcium and dextrose in the dialysate and the SiCa level at the time of the exchange.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1981

Rapid calcium release and proton uptake at the disk membrane of isolated cattle rod outer segments. 1. Stoichiometry of light-stimulated calcium release and proton uptake.

We reported a rapid, light-stimulated release of calcium from isolated rod outer segments that is apparent only when both the disk membrane and the plasma membrane are made permeable to calcium by adding the ionophore A23187 [Kaupp, U. B., Schnetkamp, P. P. M., & Junge, W. (1979) Biochim. Biophys. Acta 552, 390-403]. In this paper, we have investigated the light-sensitive diskal binding sites and the calcium release mechanism in their dependence on the pH and the presence of mono- and divalent cations, including calcium itself. We have observed now that several different rod outer segment preparations (i.e., rod outer segments with an intact plasma membrane, broken cells, and sonicated material) possess a similar dependence of their calcium release on the ionic conditions, however, only if manipulated in a way that gives access to the outer conditions of sites within disks (namely, ionophore added in the case of intact rod outer segments). Monovalent cations, at concentrations between 20 and 40 mM, suppress light-induced calcium release. Divalent and trivalent cations are more efficient inhibitors by 1-2 and 2-3 orders of magnitude, respectively. These results suggest that calcium release is controlled by an interfacial potential. The optimum pH for calcium release is pH 6.3, and virtually no release occurs beyond pH 4.5 and 9. The drop for acidic pH is attributed to the pH dependence of calcium binding to disk membranes, and the drop for alkaline pH is attributed to the pH dependence of the metarhodopsin I/metarhodopsin II transition and the light-stimulated proton uptake. In general, calcium release parallels calcium binding as a function of pH and calcium concentrations, although the release saturates at lower calcium concentrations ((KDapp = 5 microM) than would be expected from the amount of calcium bound (KD = 30-60 microM). The maximum stoichiometry is approximately 1 mol of calcium release per mol of rhodopsin bleached. Concomitant measurements of the light-stimulated uptake of protons by the disk membrane revealed a maximal stoichiometry of 2.8 mol of protons taken up per mol of rhodopsin bleached. We present an integrated description of light-stimulated calcium release, proton uptake, and changes of the interfacial potential at the disk membrane.

Animals↗
PubMed1999

Arachidonic acid induces mobilization of calcium stores and c-jun gene expression: evidence that intracellular calcium release is associated with c-jun activation.

Arachidonic acid (AA) plays a signaling role in the induction of several genes. We previously demonstrated that AA induces c-jun gene expression in the stromal cell line +/+.1 LDA 11 by a signaling pathway involving activation of the c-jun amino-terminal kinase (JNK). This study investigated the role of calcium in AA signaling of c-jun activation in +/+.1 LDA 11 cells. AA (10-50 microM) caused a rapid dose-dependent rise in cytosolic calcium. AA-induced calcium mobilization involved both influx of extracellular calcium and the release of intracellular calcium. The importance of calcium was investigated by variation of the extracellular calcium concentration, chelation of intracellular calcium and by calcium ionophore-induced influx of extracellular calcium. AA-induced c-jun gene expression and increased luciferase activity of a construct containing the high affinity AP-1 binding site was decreased in cells preincubated with the intracellular calcium chelator 1,2-bis(o-aminophenoxy)-eThane-N,N,N',N',-tetraacetic acid tetra(aceToxymethyl-esTer) (BAPTA-AM, 10 microM) prior to stimulation with AA. Similarly, chelation of intracellular calcium decreased AA-induced JNK activation. On the contrary, changes in the extracellular calcium concentration had no effect. Also, ionophore A23187 failed to induce c-jun and JNK activation either alone than in combination with AA. These results suggested that calcium was required for AA-dependent activation of c-jun, but that calcium alone was insufficient to induce activation of c-jun. Thus, release of calcium from intracellular stores is implicated in the signaling pathway of AA-induced c-jun activation in stromal cells.

Arachidonic Acid↗
PubMed1993

Effect of intravenous calcium infusion on indices of activity of the parathyroid glands and on urinary calcium and sodium excretion in normotensive and hypertensive subjects.

The effect of an intravenous calcium gluconate load (10 mg/kg over 5 min) on plasma ionized calcium concentration, parathyroid hormone (PTH), and the rate of urinary excretion of calcium, sodium, and nephrogenous cyclic adenosine monophosphate (NcAMP) was examined in 26 patients with essential hypertension and 27 age- and sex-matched normotensive subjects. Prior to calcium administration hypertensives had lower plasma ionized calcium concentration (P < .01) and higher PTH levels (P < .001) and excreted more calcium (P < .05) and NcAMP (P < .001) in the urine compared to normotensives. Following calcium infusion, plasma ionized calcium did not differ significantly between the two groups, but PTH levels remained higher in the hypertensive subjects at both 60 min (P < .001), and at 120 min (P = .02) post-load. Post-load values for both urinary calcium excretion and urinary sodium excretion were significantly higher in the hypertensive subjects than in the control group. Both before and after calcium infusion, urinary calcium excretion was positively correlated with urinary sodium excretion in each of the two groups, but for the same level of sodium excretion, hypertensives excreted more calcium in the urine, compared to normotensives, both before (P < .05) and after calcium infusion (P < .001). A positive correlation between basal plasma renin activity (PRA) values and plasma ionized calcium values obtained before (r = 0.42, P = .03) or at 60 min (r = 0.41, P = .03) and 120 min (r = 0.42, P = .03) after calcium infusion existed only in the hypertensive subject group. Post-load urinary sodium excretion values were negatively correlated to basal PRA values in both groups (r = -0.55, P < .01 and r = -0.58, P < .01 for hypertensives and normotensives, respectively), but a similar negative correlation between post-load urinary calcium excretion values and basal PRA values existed only in the hypertensive subject group (r = -0.50, P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1981

Calcium-mediated inactivation of the calcium conductance in caesium-loaded giant neurones of Aplysia californica.

1. The intracellular potassium in giant neurones of Aplysia californica was replaced with caesium by a method utilizing the ionophore nystatin. Because caesium ions have low permeability through potassium channels outward currents during voltage-clamp depolarization were strongly curtailed after the caesium loading procedure and the subsequent wash-out of the ionophore. 2. The calcium current elicited by a test voltage-clamp depolarization (pulse 2) was depressed following the entry of calcium elicited by a prior depolarization (pulse 1). 3. The percentage depression of the test current was a linear function of the pulse 1 current-time integral, and thus appears to be related linearly to the amount of calcium carried into the cell during pulse 1. This linear relation was maintained when calcium entry was varied by changes in external calcium concentration, by altered pulse 1 amplitude and altered pulse 1 duration. Depression was substantially reduced by injection of EGTA, and by substitution of barium for extracellular calcium. 4. The calcium current was unaffected by prior hyperpolarization of the membrane or by prior depolarizations to about ECa. Depression of the current was not altered by addition of extracellular 50 mM-TEA or by a strong hyperpolarization between the conditioning and test pulses. 5. The rate relaxation of the inward current during a given depolarization depended on the rate of entry and accumulation of free calcium. Relaxation under a given command potential became slower when calcium was partially replaced with magnesium so as to produce a smaller calcium current, or when accumulation of intracellular free calcium was retarded by injected EGTA or by barium substitution for extracellular calcium. 6 Evidence is considered that accumulation of calcium ions at the cytoplasmic surface of the membrane leads to inactivation through an action upon the calcium conductance. Reduced driving force and intracellular surface-charge neutralization do not adequately account for the observed depression of the calcium current resulting from intracellular accumulation of calcium ions.

Animals↗
PubMed1983

Calcium buffering and slow recovery kinetics of calcium-dependent outward current in molluscan neurones.

Calcium entry into molluscan neurones during depolarizing voltage-clamp steps activates an outward current which on repolarization decays over periods of more than 30 sec. This slowly decaying tail current was used to study the relation between calcium buffering in cytoplasm and the decline of a calcium-activated membrane process. Calcium-dependent outward current was also studied after injection of calcium into the cytoplasm. The time course of the fall of outward tail current was much less sensitive than tail current amplitude to the amount of calcium entry. Increasing bath temperature from 5 to 15 degrees C decreased the rate of fall of outward tail current activated by calcium entry. In contrast, outward current activated by calcium injection declined more rapidly at higher temperatures. Injection of sufficient EGTA to give maximum depression of outward current during depolarizations reduced the amplitude of outward tail current by at most 50%. After EGTA injection outward tail current declined more rapidly immediately following repolarization, but returned to base line at about the same time as the control. After injection of EGTA, outward current activated by calcium injection was reduced or completely blocked, and returned to base line more rapidly. Application of the mitochondrial uncoupler carbonyl cyanide m-chlorophenyl hydrazone (CCCP) did not alter the decay time course of outward tail current, but markedly prolonged the decline of outward current activated by calcium injection. The slow kinetics of outward tail current were compared to predictions of the concentration of calcium ions at the outermost surface of a spherical model cell following calcium influx. We conclude that after depolarization and calcium entry, the diffusion and binding of free calcium to cytoplasmic buffers plays a key role in determining the rate of fall of outward tail current. Further, different mechanisms influence the decline of calcium-dependent outward current following injection of calcium into the cytosol.

Animals↗
PubMed1988

Detection and separation of human red cells with different calcium contents following uniform calcium permeabilization.

1. The human red cell, permeabilized to calcium with the ionophore A23187, is extensively used to study Ca2+ transport and the effects of intracellular Ca2+ on transport and metabolism. The interpretation of results with calcium-permeabilized cells, in general, has depended on the implicit assumption that the ionophore-induced calcium distribution among the cells is uniform. 2. To establish whether or not calcium permeabilization with the ionophore A23187 generated a uniform calcium distribution in normal-ATP red cells, a method was developed to detect and separate calcium-permeabilized red cells with different calcium contents. For the method to uncover pre-existing heterogeneity without itself inducing it, it was essential to preserve the calcium distribution which existed at the time of sampling. The method was based (i) on the ability of cytoplasmic Ca2+ to activate K+-selective channels in the membrane, and (ii) on the demonstration here that thiocyanate (SCN-) is a non-limiting co-ion for rapid net KSCN efflux and cell shrinkage in the cold. 3. Calcium-permeabilized cells in pump-leak steady state were washed free of ionophore using ice-cold, albumin-containing media. Subsequent incubation at 0 degrees C in low-K+ media with 45-75 mM-SCN- generated dense-cell fractions (H cells) in less than 10 min. These could be separated from the remaining light cells (L cells) by either centrifugation over phthalate oils, or differential osmotic haemolysis, with conservation of the mean total cell calcium. 4. Analysis of the calcium content of H and L cell fractions revealed striking differences in their calcium content, with 70-99% of the mean total cell calcium in the H cell fraction. 5. The ionophore content of density-separated cells, processed with omission of the ionophore removal step, was similar for cells with high- and low-calcium. Magnesium loss from ionophore-treated red cells suspended in magnesium-free media followed single exponentials. Thus ionophore distribution and induced permeability were uniform, and the unequal cell calcium content must be due to factors affecting active calcium extrusion.

Calcimycin↗