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PubMed1995

Estimate of net calcium fluxes and sarcoplasmic reticulum calcium content during systole in rat ventricular myocytes.

1. The experiments were performed on voltage-clamped cells in which intracellular calcium concentration ([Ca2+]i) was measured with the fluorescent indicator indo-1 (acetoxymethyl ester (AM) loading). When cells were stimulated with a short (100 ms) depolarizing pulse, following a rest, the magnitude of the first systolic calcium transient was greater than that in the steady state (rest potentiation) and decayed to its steady level over a few stimuli. If a longer pulse (800 ms) was used then the systolic calcium transient was either unaffected or increased in magnitude following a rest. During constant stimulation, if the length of the pulse is decreased, then the magnitude of the calcium transient decreased reversibly over several beats. 2. The calcium entry into the cell was measured from the integral of the inward calcium current and the efflux from the Na(+)-Ca2+ exchange current on repolarization. During the negative staircase the calcium current was approximately constant whilst the Na(+)-Ca2+ exchange current decayed in parallel with the systolic calcium transient. A net loss of calcium from the cell can be calculated from the extra Na(+)-Ca2+ exchange current following the initial pulses. 3. The application of caffeine produces a transient increase of both [Ca2+]i and an inward Na(+)-Ca2+ exchange current. The integral of this current can be used to estimate the caffeine-releasable calcium content of the sarcoplasmic reticulum (SR), which decreases following stimulation with short compared to long pulses. This difference in SR calcium content is quantitatively similar to that estimated from the sarcolemmal currents. 4. At a given membrane potential, the relationship between [Ca2+]i and current during the caffeine exposure can be used to estimate the Na(+)-Ca2+ exchange flux from the measured [Ca2+]i and thence the Na(+)-Ca2+ exchange flux during depolarization. 5. For a long depolarizing pulse the extrusion of calcium from the cell on Na(+)-Ca2+ exchange is comparable to the entry on the calcium current. In contrast, for short pulses the extrusion of calcium on the Na(+)-Ca2+ exchange immediately after the pulse is greater than the entry during the pulse on the calcium current. 6. These results show that rest potentiation can be correlated with changes in the amount of calcium stored in the SR and this, in turn, can be accounted for by sarcolemmal fluxes.

Animals↗
PubMed2005

Carboxyamidotriazole-induced inhibition of mitochondrial calcium import blocks capacitative calcium entry and cell proliferation in HEK-293 cells.

Blocking calcium entry may prevent normal and pathological cell proliferation. There is evidence suggesting that molecules such as carboxyamidotriazole, widely used in anti-cancer therapy based on its ability to block calcium entry in nonexcitable cells, also have antiproliferative properties. We found that carboxyamidotriazole and the capacitative calcium entry blocker 2-aminoethoxydiphenyl borate inhibited proliferation in HEK-293 cells with IC50 values of 1.6 and 50 microM, respectively. Capacitative calcium entry is activated as a result of intracellular calcium store depletion. However, non-capacitative calcium entry pathways exist that are independent of store depletion and are activated by arachidonic acid and diacylglycerol, generated subsequent to G protein coupled receptor stimulation. We found that carboxyamidotriazole completely inhibited the capacitative calcium entry and had no effect on the amplitude of arachidonic-acid-activated non-capacitative calcium entry. However, investigation of the effects of carboxyamidotriazole on mitochondrial calcium dynamics induced by carbachol, capacitative calcium entry and exogenously set calcium loads in intact and digitonin-permeabilized cells revealed that carboxyamidotriazole inhibited both calcium entry and mitochondrial calcium uptake in a time-dependent manner. Mitochondrial inner-membrane potential was altered by carboxyamidotriazole treatment, suggesting that carboxyamidotriazole antagonizes mitochondrial calcium import and thus local calcium clearance, which is crucial for the maintenance of capacitative calcium entry.

Boron Compounds↗
PubMed1989

Barium ions enter chromaffin cells via voltage-dependent calcium channels and induce secretion by a mechanism independent of calcium.

Barium ions enter chromaffin cells via voltage-sensitive calcium channels, although the intracellular site of barium action is distinct from that of calcium. The entry of barium primarily through voltage-sensitive channels was indicated by experiments showing inhibition of 133Ba2+ uptake by blockers of voltage-dependent calcium channels. In addition, 133Ba2+ uptake was stimulated by 50 mM KCl but not by nicotine. Furthermore, 133Ba2+ uptake was inhibited by hyperosmolarity, which specifically blocks the voltage-sensitive calcium channel but not the receptor-associated calcium channel. These conclusions from studies on barium uptake were also borne out by experiments measuring catecholamine secretion. Thus, blockers of voltage-dependent calcium channels which inhibited barium uptake also inhibited barium-induced catecholamine secretion. In other experiments, simultaneous stimulation with nicotine and barium in the presence of calcium evoked coincident and additive catecholamine secretion. By contrast, when 50 mM KCl was substituted for nicotine in the same experimental design, barium ions inhibited potassium-induced catecholamine secretion at low calcium concentrations. Only at high calcium concentrations were barium-induced and potassium-induced secretion additive. These data also indicate that barium and calcium compete at the voltage-sensitive pathway. Furthermore, these additivity data suggest that once inside the cell, barium and calcium have two distinct mechanisms of action. As predicted by this hypothesis, in digitonin-permeabilized chromaffin cells either calcium or barium stimulated catecholamine release, and in the presence of both cations catecholamine secretion was equivalent to the sum of secretion with either cation alone. Additional support of this concept comes from experiments showing that while calcium-mediated catecholamine secretion is sensitive to trifluoperazine and imipramine, barium-mediated secretion is not. Taken together, all these data indicate that there are two distinct intracellular sites of action for barium and calcium. In contrast to catecholamine secretion, non-exocytotic ascorbic acid secretion was induced by nicotine and potassium in the presence of calcium, but not by barium alone. These data provide additional evidence that barium acts by a different mechanism than calcium, in still another secretory system in chromaffin cells.

Animals↗
PubMed1989

Effect of sepsis on calcium uptake and content in skeletal muscle and regulation in vitro by calcium of total and myofibrillar protein breakdown in control and septic muscle: results from a preliminary study.

Because high calcium concentration in vitro stimulates muscle proteolysis, calcium has been implicated in the pathogenesis of increased muscle breakdown in different catabolic conditions. Protein breakdown in skeletal muscle is increased during sepsis, but the effect of sepsis on muscle calcium uptake and content is not known. In this study the influence of sepsis, induced in rats by cecal ligation and puncture, on muscle calcium uptake and content was studied. Sixteen hours after cecal ligation and puncture or sham operation, calcium content of the extensor digitorum longus (EDL) and soleus (SOL) muscles was determined with an atomic absorption spectrometer. Calcium uptake was measured in intact SOL muscles incubated in the presence of calcium 45 (45Ca) for between 1 and 120 minutes. Total and myofibrillar protein breakdown was determined in SOL muscles, incubated in the presence of different calcium concentrations (0; 2.5; 5.0 mmol/L), and measured as release into the incubation medium of tyrosine and 3-methylhistidine (3-MH), respectively. Calcium content was increased by 51% (p less than 0.001) during sepsis in SOL and by 10% (p less than 0.05) in EDL muscle. There was no difference in 45Ca uptake between control and septic muscles during the early phase (1 to 5 minutes) of incubation. During more extended incubation (30 to 120 minutes), muscles from septic rats took up significantly more 45Ca than control muscles (p less than 0.05). Tyrosine release by incubated SOL muscles from control and septic rats was increased when calcium was added to the incubation medium, and at a calcium concentration of 2.5 mmol/L, the increase in tyrosine release was greater in septic than in control muscle. Addition of calcium to the incubation medium did not affect 3-MH release in control or septic muscle. The results suggest that calcium uptake and content in skeletal muscle are increased during sepsis and that high calcium concentrations in vitro stimulate nonmyofibrillar protein breakdown. Muscles from septic animals may be more sensitive to the effect of calcium in vitro than muscles from nonseptic rats. Whether increased calcium uptake and content in skeletal muscle is partly responsible for accelerated muscle proteolysis during sepsis remains to be determined.

Animals↗
PubMed2005

Calcium absorption from corn tortilla is relatively high and is dependent upon calcium content and liming in Mexican women.

Corn tortillas are the staple food of Mexico. During their preparation, calcium is added to the tortillas; therefore, tortillas are the main source of calcium for a large proportion of the population. The bioavailability of calcium from lime-treated tortillas in humans is not known. The objectives of the present study were to determine calcium absorption from corn tortilla, to determine the effect of lime treatment on calcium absorption from corn tortilla, and to compare calcium absorption from tortilla prepared with a commercial corn flour and tortillas prepared with the traditional lime treatment at home. Nonpregnant, nonlactating women (n = 9) were administered 3 different treatments: 1) 180 g of corn tortilla prepared from corn flour with no lime treatment (CF), 2) 180 g of corn tortilla prepared from lime-treated commercial corn flour (LTCCF), or 3) 180 g of corn tortillas prepared from lime-treated home-prepared corn flour (LTHCF). Calcium absorption was measured using an established dual-tracer stable isotope technique. Calcium absorption of CF, LTCCF, and LTHCF was (mean +/- SD): 44 +/- 3.2, 32 +/- 4.4, and 30 +/- 2.4%, respectively; the fractional calcium absorption from CF differed from that of either LTCCF or LTHCF (P < 0.01). The total amount of calcium absorbed per treatment was higher in LTHCF (98.10 mg +/- 21.7) than in LTCCF (59.9 mg +/- 23.7, P < 0.001) and CF (3.78 mg +/- 0.9, P < 0.0.001). In conclusion, calcium absorption from corn tortillas is high and dependent on calcium concentration. The addition of calcium during lime treatment increases calcium concentration and total calcium absorption.

Absorption↗
PubMed2006

Comparative genomic and phylogenetic analyses of calcium ATPases and calcium-regulated proteins in the apicomplexa.

The phylum Apicomplexa comprises a large group of early branching eukaryotes that includes a number of human and animal parasites. Calcium controls a number of vital processes in apicomplexans including protein secretion, motility, and differentiation. Despite the importance of calcium as a second messenger, very little is known about the systems that control homeostasis or that regulate calcium signaling in parasites. The recent completion of many apicomplexan genomes provides new opportunity to define calcium response pathways in this group of parasites in comparison to model organisms. Whole-genome comparison between the apicomplexans Plasmodium spp., Cryptosporidium spp., and Toxoplasma gondii revealed the presence of several P-Type Ca2+ transporting ATPases including a single endoplasmic reticulum (ER)-type sarcoplasmic-endoplasmic reticulum Ca2+ ATPase, several Golgi-like Ca2+ ATPases, and a single Ca2+/H+ exchanger. Only T. gondii showed evidence of plasma membrane-type Ca2+ ATPases or voltage-gated calcium channels. Despite pharmacological evidence for IP3 and ryanodine-mediated calcium release, animal-type calcium channels were not readily identified in parasites, indicating they are more similar to plants. Downstream of calcium release, a variety of EF-hand-containing proteins regulate calcium responses. Our analyses detected a single conserved calmodulin (CaM) homologue, 3 distinct centrin (CETN)-caltractin-like proteins, one of which is shared with ciliates, and a variety of deep-branching, CaM-CETN-like proteins. Apicomplexans were also found to contain a wide array of calcium-dependent protein kinases (CDPKs), which are commonly found in plants. Toxoplasma gondii contains more than 20 CDPK or CDPK-related kinases, which likely regulate a variety of responses including secretion, motility, and differentiation. Genomic and phylogenetic comparisons revealed that apicomplexans contain a variety of unusual calcium response pathways that are distinct from those seen in vertebrates. Notably, plant-like pathways for calcium release channels and calcium-dependent kinases are found in apicomplexans. The experimental flexibility of T. gondii should allow direct experimental manipulation of these pathways to validate their biological roles. The central importance of calcium in signaling and development, and the novel characteristics of many of these systems, indicates that parasite calcium pathways may be exploited as new therapeutic targets for intervention.

Amino Acid Sequence↗
PubMed2004

Calcium-activated potassium channels are selectively coupled to P/Q-type calcium channels in cerebellar Purkinje neurons.

Cerebellar Purkinje neurons fire spontaneously in the absence of synaptic transmission. P/Q-type voltage-gated calcium channels and calcium-activated potassium channels are required for normal spontaneous activity. Blocking P/Q-type calcium channels paradoxically mimics the effects of blocking calcium-activated potassium channels. Thus, an important function of the P/Q-type calcium channels is to provide calcium for activation of calcium-activated potassium channels. Purkinje neurons express several classes of voltage-gated calcium channels, and the P/Q- and T-type channels make comparable contributions to total calcium entry after an action potential. Here we demonstrate that calcium-activated potassium channels are activated exclusively by calcium entering through P/Q-type voltage-gated calcium channels. This selective coupling is maintained even when calcium flux through voltage-gated channels is increased by increasing the extracellular calcium concentration. Small decreases in P/Q current density are likely to alter spontaneous activity of Purkinje neurons via decreased recruitment of calcium-activated potassium channels. In both human and murine animal models, mutations that decrease P/Q current density in Purkinje neurons also cause cerebellar ataxia. Alterations in the spontaneous activity of Purkinje neurons may be an important contributing factor to the ataxia in these subjects.

Action Potentials↗
PubMed1999

Fast calcium-dependent inactivation of calcium release-activated calcium current (CRAC) in RBL-1 cells.

Fast inactivation of the Ca2+ release-activated Ca2+ current (ICRAC) was studied using whole cell patch-clamp recordings in rat basophilic leukemia (RBL-1) cells. Application of hyperpolarizing voltage steps from the holding potential of 0 mV revealed that ICRAC declined in amplitude over tens of milliseconds during steps more negative than -40 mV. This fast inactivation was predominantly Ca2+-dependent because first, it could be more effectively suppressed when BAPTA was included in the recording pipette instead of EGTA and second, replacing external Ca2+ with Sr2+ resulted in less inactivation. Recovery from inactivation was faster in the presence of BAPTA than EGTA. The extent of fast inactivation was independent of the whole cell ICRAC amplitude, compatible with the notion that the inactivation arose from a local feedback inhibition by permeating Ca2+ ions only on the channel it permeated. Ca2+ release from stores did not affect fast inactivation, nor did FCepsilonRI receptor stimulation. Current clamp recordings showed that the majority of RBL cells had a membrane potential close to -90 mV following stimulation of FCepsilonRI receptors. Hence fast inactivation is likely to impact on the extent of Ca2+ influx through CRAC channels under physiological conditions and appears to be an important negative feedback process that limits Ca2+ increases.

Animals↗
PubMed2006

Role of calcium influx through voltage-operated calcium channels and of calcium mobilization in the physiology of Schistosoma mansoni muscle contractions.

We tested the hypothesis that voltage-operated Ca2+ channels mediate an extracellular Ca2+ influx in muscle fibres from the human parasite Schistosoma mansoni and, along with Ca2+ mobilization from the sarcoplasmic reticulum, contribute to muscle contraction. Indeed, whole-cell voltage clamp revealed voltage-gated inward currents carried by divalent ions with a peak current elicited by steps to +20 mV (from a holding potential of -70 mV). Depolarization of the fibres by elevated extracellular K+ elicited contractions that were completely dependent on extracellular Ca2+ and inhibited by nicardipine (half inhibition at 4.1 microM). However these contractions were not very sensitive to other classical blockers of voltage-gated Ca2+ channels, indicating that the schistosome muscle channels have an atypical pharmacology when compared to their mammalian counterparts. Futhermore, the contraction induced by 5 mM caffeine was inhibited after depletion of the sarcoplasmic reticulum either with thapsigargin (10 microM) or ryanodine (10 microM). These data suggest that voltage-operated Ca2+ channels do contribute to S. mansoni contraction as does the mobilization of stored Ca2+, despite the small volume of sarcoplasmic reticulum in schistosome smooth muscles.

Animals↗
PubMed2002

Calcium-dependent inactivation and depletion of synaptic cleft calcium ions combine to regulate rod calcium currents under physiological conditions.

L-type Ca2+ currents (I(Ca)) in rod photoreceptors exhibit Ca2+-dependent inactivation. Perforated-patch whole-cell recordings were obtained from isolated rods of the tiger salamander using 1.8 mm Ca2+ in the bathing medium to determine the extent of Ca2+-dependent inactivation of I(Ca) with physiological [Ca2+] and endogenous buffering. I(Ca) was measured with voltage ramps applied before and after 5-s steps to -40, -30, -20, or -10 mV. Long depolarizing steps in isolated rods produced inactivation of I(Ca) ranging from 15% at -40 mV to > 80% at -10 mV. Because, in addition to Ca2+-dependent inactivation, depletion of synaptic cleft Ca2+ accompanying activation of I(Ca) can reduce presynaptic I(Ca) at calycal synapses, we investigated whether a similar mechanism worked at the invaginating rod synapse. Rods from retinal slices with intact synapses were compared with isolated rods in which synaptic cleft depletion is absent. I(Ca) was more strongly depressed by depolarization of rods in retinal slices, with ICa reduced by 47% following voltage steps to -40 mV. The depression of currents by depolarization was also greater for rods from retinal slices than isolated rods when Ca2+ was replaced with Ba2+ to reduce Ca2+-dependent inactivation. The stronger depolarization-evoked inhibition of I(Ca) in retinal slices compared to isolated rods probably reflects depletion of synaptic cleft Ca2+ arising from sustained Ca2+ influx. Inactivation of I(Ca) exhibited slow onset and recovery. These findings suggest that Ca2+-dependent inactivation and depletion of synaptic cleft Ca2+ may combine to regulate I(Ca) in response to light-evoked changes in rod membrane potential.

Ambystoma↗
PubMed1998

Slow feedback inhibition of calcium release-activated calcium current by calcium entry.

In many nonexcitable cells, depletion of the inositol 1,4, 5-trisphosphate-sensitive store activates Ca2+ influx, a process termed store-operated Ca2+ entry. In rat basophilic leukemia cells, emptying of the stores activates a highly selective Ca2+ release-activated Ca2+ current (CRAC), ICRAC. We have recently found that ICRAC activates in an essentially all-or-none manner when the current is evoked by receptor stimulation, dialysis with inositol 1, 4,5-trisphosphate via the patch pipette, or through the Ca2+ATPase inhibitor thapsigargin (Parekh, A. B., Fleig, A., and Penner, R. (1997) Cell 89, 973-980). Regulatory mechanisms must therefore operate to control the overall amount of Ca2+ that enters through CRAC channels. Such mechanisms include membrane potential and protein kinase C. In the present study, we have investigated additional inhibitory pathways that serve to determine just how much Ca2+ can enter through ICRAC. We have directly measured the current using the whole cell patch clamp technique. We report the presence of a slow Ca2+-dependent inactivation mechanism that curtails Ca2+ entry through CRAC channels. This inactivation mechanism is switched on by Ca2+ entering through CRAC channels, and therefore constitutes a slow negative feedback process. Although it requires a rise in intracellular Ca2+ for activation, it maintains CRAC channels inactive even under conditions that lower intracellular Ca2+ levels. The inactivation mechanism does not involve store refilling, protein phosphorylation, G proteins, nor Ca2+-dependent enzymes. It accounts for up to 70% of the total inactivation of ICRAC, and therefore appears to be a dominant inhibitory mechanism. It is likely to be an important factor that shapes the profile of the Ca2+ signal in these nonexcitable cells.

Animals↗
PubMed2000

Calreticulin couples calcium release and calcium influx in integrin-mediated calcium signaling.

The engagement of integrin alpha7 in E63 skeletal muscle cells by laminin or anti-alpha7 antibodies triggered transient elevations in the intracellular free Ca(2+) concentration that resulted from both inositol triphosphate-evoked Ca(2+) release from intracellular stores and extracellular Ca(2+) influx through voltage-gated, L-type Ca(2+) channels. The extracellular domain of integrin alpha7 was found to associate with both ectocalreticulin and dihydropyridine receptor on the cell surface. Calreticulin appears to also associate with cytoplasmic domain of integrin alpha7 in a manner highly dependent on the cytosolic Ca(2+) concentration. It appeared that intracellular Ca(2+) release was a prerequisite for Ca(2+) influx and that calreticulin associated with the integrin cytoplasmic domain mediated the coupling of between the Ca(2+) release and Ca(2+) influx. These findings suggest that calreticulin serves as a cytosolic activator of integrin and a signal transducer between integrins and Ca(2+) channels on the cell surface.

Animals↗
PubMed1993

Redundant mechanisms of calcium-induced calcium release underlying calcium waves during fertilization of sea urchin eggs.

Propagating Ca2+ waves are a characteristic feature of Ca(2+)-linked signal transduction pathways. Intracellular Ca2+ waves are formed by regenerative stimulation of Ca2+ release from intracellular stores by Ca2+ itself. Mechanisms that rely on either inositol trisphosphate or ryanodine receptor channels have been proposed to account for Ca2+ waves in various cell types. Both channel types contributed to the Ca2+ wave during fertilization of sea urchin eggs. Alternative mechanisms of Ca2+ release imply redundancy but may also allow for modulation and diversity in the generation of Ca2+ waves.

Adenosine Diphosphate Ribose↗