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At least 433 records · Page 24Linked to original sources
PubMed2004

Calcium channels are involved in calcium oxalate crystal formation in specialized cells of Pistia stratiotes L.

BACKGROUND AND AIMS: Pistia stratiotes produces large amounts of calcium (Ca) oxalate crystals in specialized cells called crystal idioblasts. The potential involvement of Ca(2+) channels in Ca oxalate crystal formation by crystal idioblasts was investigated. METHODS: Anatomical, ultrastructural and physiological analyses were used on plants, fresh or fixed tissues, or protoplasts. Ca(2+) uptake by protoplasts was measured with (45)Ca(2+), and the effect of Ca(2+) channel blockers studied in intact plants. Labelled Ca(2+) channel blockers and a channel protein antibody were used to determine if Ca(2+) channels were associated with crystal idioblasts. KEY RESULTS: (45)Ca(2+) uptake was more than two orders of magnitude greater for crystal idioblast protoplasts than mesophyll protoplasts, and idioblast number increased when medium Ca was increased. Plants grown on media containing 1-50 microM of the Ca(2+) channel blockers, isradipine, nifedipine or fluspirilene, showed almost complete inhibition of crystal formation. When fresh tissue sections were treated with the fluorescent dihydropyridine-type Ca(2+) channel blocker, DM-Bodipy-DHP, crystal idioblasts were intensely labelled compared with surrounding mesophyll, and the label appeared to be associated with the plasma membrane and the endoplasmic reticulum, which is shown to be abundant in idioblasts. An antibody to a mammalian Ca(2+) channel alpha1 subunit recognized a single band in a microsomal protein fraction but not soluble protein fraction on western blots, and it selectively and heavily labelled developing crystal idioblasts in tissue sections. CONCLUSIONS: The results demonstrate that Ca oxalate crystal idioblasts are enriched, relative to mesophyll cells, in dihydropyridine-type Ca(2+) channels and that the activity of these channels is important to transport and accumulation of Ca(2+) required for crystal formation.

Araceae↗
PubMed1986

Calcium metabolism, renin activity, and the antihypertensive effects of calcium channel blockade.

Although abnormalities of calcium metabolism have been described in various hypertensive states, the specific manner in which these abnormalities contribute to the increased pressure remains unclear. Our own group, in attempting to resolve the seemingly contradictory evidence thus far obtained, has adopted an approach emphasizing the clinical as well as biochemical heterogeneity among hypertensive subjects. We have observed the following: broad-based deviations of calcium ionic and hormonal indices in patients with essential hypertension; these deviations are linked with concurrent deviations in the renin-aldosterone system. Thus, low-renin subjects exhibit a calcium ionic and hormonal profile suggestive of calcium deficiency, whereas high-renin subjects have an opposite metabolic profile suggestive of calcium excess; blood pressure responses to dietary salt loading may also differ among renin subgroups of essential hypertension and may be mediated by salt-induced alterations of calcium metabolism. In the absence of these alterations, dietary salt intake results in little or no change in blood pressure; and calcium as a dietary supplement may itself possess antihypertensive properties in targeted subgroups of essential hypertensive patients, preferentially in low-renin, lower ionized calcium subjects. Interestingly, calcium channel blockade also preferentially lowers pressure in low-renin, lower serum ionized calcium forms of hypertension and may define those subjects whose elevated pressure is most dependent on extracellular calcium. Conversely, renin profiling or serum ionized calcium measurements may be used clinically to help target subjects most likely to benefit from calcium channel antagonists. Lastly, unlike other antihypertensive drug classes, high salt intake does not blunt, and may even enhance, the hypotensive effects of calcium channel blockade, lessening the need for stringent dietary recommendations. Altogether, these heterogeneous alterations of calcium metabolism in essential hypertension suggest that the linkage between the regulation of calcium metabolism, renin system activity, and blood pressure in essential hypertension is of pathophysiologic as well as therapeutic relevance.

Blood Pressure↗
PubMed1986

Calcium channel blockade and renal function.

Since calcium channel blocking agents were introduced into the treatment of hypertension their influence on renal function has become an important issue. In animal experiments calcium channel blocking agents have been shown to increase renal blood flow and glomerular filtration rate and to augment urine flow and electrolyte excretion. In human acute studies the administration of calcium channel blocking agents have elicited similar renal hemodynamic and diuretic effects. Clinical studies on the renal effects of long-term treatment are however still lacking. Studies on the effect on renin release have given divergent results. In acute experiments renin release is increased by calcium channel blocking agents. In long-term treatment, however, no change in peripheral plasma levels of renin has been demonstrated. The influence of decreased renal function on the pharmacokinetics of calcium channel blocking agents has been studied in patients with renal disease. For verapamil the volume of distribution is smaller in uremic patients than in normals and both metabolic and renal clearances are decreased. For nifedipine, on the other hand, similar plasma levels, plasma half life and total plasma clearance are found in uremic patients and normal subjects.

Animals↗
PubMed1997

The voltage-dependent non-selective cation channel sensitive to the L-type calcium channel blocker efonidipine regulates Ca2+ influx in brain vascular smooth muscle cells.

The present study investigated the ion channel responsible Ca2+ influx in cultured smooth muscle cells from bovine brain arteries by monitoring Ba2+ currents. Voltage pulses at a range between -100 and +100 mV from a holding potential of 0 mV induced currents and the current/voltage (I/V) relations were linear with a reversal potential of +/- 0 mV. The currents were increased by elevating extracellular Ba2+ concentrations, suggesting that the voltage-sensitive non-selective cation channel, which favors Ca2+ influx, is expressed in brain vascular smooth muscle cells. In contrast, when voltage pulses at a range between -50 to +50 mV from a holding potential of -80 mV were applied to carotid smooth muscle cells, inward currents were evoked by depolarization to > or = -10 mV and the I/V relations were bell-shaped, typical for the L-type calcium channels. The dihydropyridine derivatives, efonidipine and nicardipine, inhibited the L-type Ca2+ channel-operated currents in carotid smooth muscles, and further efonidipine had an inhibitory effect also on non-selective cation currents in brain vascular smooth muscle cells. These results suggest that the voltage-dependent non-selective cation channel expressed in brain vascular smooth muscle cells is sensitive to a kind of the dihydropyridine derivatives and regulates Ca2+ influx.

Animals↗
PubMed2003

In vivo analysis of voltage-dependent calcium channels.

The molecular cloning of calcium channel subunits has identified an unexpectedly large number of genes and splicing variants, many of whichhave complex expression patterns: a central problem of calcium channel biology is to understand the functional significance of this genetic complexity. The genetic analysis of voltage-dependent calcium channels (VDCCs) provides an approach to defining channel function that is complimentary to pharmacological, electrophysiological, and other molecular methods. By discovering or creating alleles of VDCC genes, one can gain an understanding of the VDCC function at the whole animal level. Of particular interest are mutations in the alpha1 genes that encode the pore forming subunits, as they define the specific channel subtypes. In fact, a variety of calcium channelopathies and targeted mutations have been described for these genes in the last 6 years. The mutant alleles described below illustrate how phenotype analysis of these alleles has uncovered very specific functional roles that can be localized to specific synapses or cells.

Amino Acid Sequence↗
PubMed1993

New uses for calcium channel blockers. Therapeutic implications.

Calcium antagonists block calcium entry into cells, resulting in relaxation of smooth muscle and limitation of the cytotoxic effects of ischaemia in various organ systems. They are most frequently used for clinical conditions requiring vasodilatation, i.e. hypertension and Raynaud's phenomenon, and this also suggests that the most common adverse effect of these drugs for noncardiovascular indications is an unwanted decline in blood pressure. Other uses include treatment of supraventricular arrhythmias and angina. There is some evidence that these drugs retard the development of atherosclerosis. Calcium channel blockers also improve renal reperfusion and may reduce renal insufficiency due to various nephrotoxins, and are particularly useful in renal transplantation for protection against cyclosporin toxicity and post-transplant acute tubular necrosis. These drugs are also useful in pregnancy-induced hypertension and unwanted uterine contraction. Affective disorders and malignancies may be other conditions which benefit from calcium antagonist therapy. Calcium antagonists, in particular nimodipine which is most selective for the cerebral vasculature, have been approved for treating vasospasm after subarachnoid haemorrhage. They are probably also effective for treatment of migraine. Calcium channel blockers may be effective for treating acute cerebral infarction, but results of clinical trials to date have been equivocal, largely because it has been difficult to recruit patients within the short interval after the onset of stroke when these drugs would be most effective, and because of the unwanted hypotensive effect of high doses.

Animals↗
PubMedDate not supplied

[Molecular diversity of calcium channel activities by depolarization].

Voltage-gated calcium channels are involved in a large variety of cellular functions such as excitation-contraction coupling, hormone secretion, firing and pacemaker activity, gene activation and proliferation. Cloning of complementary DNAs encoding for calcium channel subunits has challenged the study of the functional properties of calcium channels and has allowed analysis of the molecular basis of calcium channel diversity. Recently, pore-forming subunits of T-type calcium channels have been cloned. Recent data describing the genes encoding calcium channels, their molecular and pharmacological studies, as well as their linkage to human genetic diseases are reviewed in this article.

Animals↗
PubMed2004

Lack of delta waves and sleep disturbances during non-rapid eye movement sleep in mice lacking alpha1G-subunit of T-type calcium channels.

T-type calcium channels have been implicated as a pacemaker for brain rhythms during sleep but their contribution to behavioral states of sleep has been relatively uncertain. Here, we found that mice lacking alpha1(G) T-type Ca(2+) channels showed a loss of the thalamic delta (1-4 Hz) waves and a reduction of sleep spindles (7-14 Hz), whereas slow (<1 Hz) rhythms were relatively intact, when compared with the wild-type during urethane anesthesia and non-rapid eye movement (NREM) sleep. Analysis of sleep disturbances, as defined by the occurrence of brief awakening (BA) episodes during NREM sleep, revealed that mutant mice exhibited a higher incidence of BAs of >16 sec compared with the wild-type, whereas no difference was seen in BAs of <16 sec between the two genotypes. These results are consistent with the previous idea of the distinct nature of delta oscillations and sleep spindles from cortically generated slow waves. These results also suggest that the alpha1(G)-subunit of T-type calcium channels plays a critical role in the genesis of thalamocortical oscillations and contributes to the modulation of sleep states and the transition between NREM sleep and wake states.

Animals↗
PubMed2004

Folding of active calcium channel beta(1b) -subunit by size-exclusion chromatography and its role on channel function.

Voltage-gated calcium channels mediate the influx of Ca(2+) ions into eukaryotic cells in response to membrane depolarization. They are hetero-multimer membrane proteins formed by at least three subunits, the poreforming alpha(1)-subunit and the auxiliary beta- and alpha(2)delta-subunits. The beta-subunit is essential for channel performance because it regulates two distinct features of voltage-gated calcium channels, the surface expression and the channel activity. Four beta-subunit genes have been cloned, beta(1-4), with molecular masses ranging from 52 to 78 kDa, and several splice variants have been identified. The beta(1b)-subunit, expressed at high levels in mammalian brain, has been used extensively to study the interaction between the pore forming alpha(1)- and the regulatory beta-subunit. However, structural characterization has been impaired for its tendency to form aggregates when expressed in bacteria. We applied an on-column refolding procedure based on size exclusion chromatography to fold the beta(1b)-subunit of the voltage gated-calcium channels from Escherichia coli inclusion bodies. The beta(1b)-subunit refolds into monomers, as shown by sucrose gradient analysis, and binds to a glutathione S-transferase protein fused to the known target in the alpha(1)-subunit (the alpha-interaction domain). Using the cut-open oocyte voltage clamp technique, we measured gating and ionic currents in Xenopus oocytes expressing cardiac alpha(1)-subunit (alpha(1C)) co-injected with folded-beta(1b)-protein or beta(1b)-cRNA. We demonstrate that the co-expression of the alpha(1C)-subunit with either folded-beta(1b)-protein or beta(1b)-cRNA increases ionic currents to a similar extent and with no changes in charge movement, indicating that the beta(1b)-subunit primarily modulates channel activity, rather than expression.

Alternative Splicing↗
PubMed2000

Combinatorial synthesis of omega-conotoxin MVIIC analogues and their binding with N- and P/Q-type calcium channels.

Omega-conotoxin MVIIC (MVIIC) blocks P/Q-type calcium channels with high affinity and N-type calcium channels with low affinity, while the highly homologous omega-conotoxin MVIIA blocks only N-type calcium channels. We wished to obtain MVIIC analogues more selective for P/Q-type calcium channels than MVIIC to elucidate structural differences among the channels, which discriminate the omega-conotoxins. To prepare a number of MVIIC analogues efficiently, we developed a combinatorial method which includes a random air oxidation step. Forty-seven analogues were prepared in six runs and some of them exhibited higher selectivity for P/Q-type calcium channels than MVIIC in binding assays.

Amino Acid Sequence↗
PubMed1996

How do calcium channel blockers prevent cardiovascular events. Are they all alike?

The calcium channel blockers (calcium antagonists) have vasodilatory and cardiodepressant effects. These pharmacological properties explain, to a large extent, the antihypertensive, antianginal, and antiarrhythmic effects of these agents. Pharmacological differences between members of this class, e.g. differences in vascular selectivity, are well documented and can be exploited clinically. The efficacy of calcium channel blockers in the prevention of cardiovascular events may depend on factors other than their vasodilatory and cardiodepressive effects. Much interest, for example, has been shown in their possible antiatherosclerotic effects. It is, however, at present not possible to ascertain how important these and other ancillary effects (such as plaque stabilisation) are for the putative cardioprotective effects of calcium channel blockers. There are, moreover, few in vitro or in vivo (animal or clinical) studies allowing valid comparison of the different calcium channel blockers with regard to these ancillary properties.

Animals↗
PubMed1992

Will the calcium channel agonist BAY K8644 inhibit halothane-induced impairment of calcium current?

The inhaled anesthetics impair transsarcolemmal calcium entry (ICa) in myocardial cells, although the mechanism of this interaction is not known. This inhibition of calcium entry has been implicated in the myocardial depression of the volatile anesthetics. To further characterize this interaction and to evaluate whether a calcium channel agonist could attenuate or prevent the inhibition of calcium entry, the effect of the calcium channel agonist BAY K8644 on the impairment of ICa by halothane was evaluated in single guinea pig ventricular myocytes. Calcium currents were evoked by means of the whole-cell voltage-clamp technique. Baseline peak ICa was higher in the cells exposed to 5 microM BAY K8644 (311 vs 206 pA/cm2, P less than 0.04). On exposure to 1% halothane, peak ICa was impaired to an identical degree whether or not cells were exposed to BAY K8644 (78% and 79% of baseline value). This is consistent with the suggestion that the effects of these agents on ICa are nonspecific. However, the increase in ICa suggests that appropriate calcium channel agonists might serve to ameliorate the myocardial depressant effects of halothane.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1999

High sensitivity of immature GABAergic neurons to blockers of voltage-gated calcium channels.

The involvement of voltage-gated calcium channels in the survival of immature CNS neurons was studied in aggregating brain cell cultures by examining cell type-specific effects of various channel blockers. Nifedipine (10 microM), a specific blocker of L-type calcium channels, caused a pronounced and irreversible decrease of glutamic acid decarboxylase activity, whereas the activity of choline acetyltransferase was significantly less affected. Flunarizine (1-10 microM, a relatively unspecific ion channel blocker) elicited similar effects, that were attenuated by NMDA. The glia-specific marker enzymes, glutamine synthetase and 2',3'-cyclic nucleotide 3'-phosphohydrolase, were affected only after treatment with high concentrations of nifedipine (50 microM) or NiCl2 (100 microM, shown to block T-type calcium channels). Nifedipine (50 microM), NiCl2 (100 microM), and flunarizine (5 microM) also caused a significant increase in the soluble nucleosome concentration, indicating increased apoptotic cell death. This effect was prevented by cycloheximide (1 microM). Furthermore, the combined treatment with calcicludine (10 nM, blocking L-type calcium channels) and funnel-web spider toxin-3.3 (100 nM, blocking T-type channels) also caused a significant increase in free nucleosomes as well as a decrease in glutamic acid decarboxylase activity. In contrast, cell viability was not affected by peptide blockers specific for N-, P-, and/or Q-type calcium channels. Highly differentiated cultures showed diminished susceptibility to nifedipine and flunarizine. The present data suggest that the survival of immature neurons, and particularly that of immature GABAergic neurons, requires the sustained entry of Ca2+ through voltage-gated calcium channels.

Acetylcholine↗
PubMed1989

Calcium channel modulators: effects on gastric function.

Calcium is important in stimulus-secretion coupling in the gut. We therefore examined a dihydropyridine (nitrendipine), a phenylalkylamine (verapamil) and a benzothiazepine (diltiazem) calcium channel blocker as well as a calcium channel 'agonist', CGP 28392, in several models of gastric function. Nitrendipine significantly decreased stress-induced gastric lesions, but was far less efficacious against 100% ethanol-induced lesions. The anti-ulcer effects of nitrendipine were not reversible with indomethacin, sodium meclofenamate or N-ethylmaleimide. Nitrendipine also significantly reduced basal gastric acid output. Verapamil significantly reduced stress lesions in an indomethacin and meclofenamate-reversible manner, but worsened ethanol ulcers. Verapamil also decreased basal acid secretion. Diltiazem decreased stress lesions (indomethacin- and meclofenamate-reversible), worsened ethanol lesions and slightly reduced acid secretion. CGP 28392 exerted a modest stress gastroprotective effect, decreased ethanol lesions and reduced slightly basal acid secretion. A possible clinical role for gastric calcium channel blockade is raised by these results.

Animals↗
PubMed2002

Pain perception in mice lacking the beta3 subunit of voltage-activated calcium channels.

The importance of voltage-activated calcium channels in pain processing has been suggested by the spinal antinociceptive action of blockers of N- and P/Q-type calcium channels as well as by gene targeting of the alpha1B subunit (N-type). The accessory beta3 subunits of calcium channels are preferentially associated with the alpha1B subunit in neurones. Here we show that deletion of the beta3 subunit by gene targeting affects strongly the pain processing of mutant mice. We pinpoint this defect in the pain-related behavior and ascending pain pathways of the spinal cord in vivo and at the level of calcium channel currents and proteins in single dorsal root ganglion neurones in vitro. The pain induced by chemical inflammation is preferentially damped by deletion of beta3 subunits, whereas responses to acute thermal and mechanical harmful stimuli are reduced moderately or not at all, respectively. The defect results in a weak wind-up of spinal cord activity during intense afferent nerve stimulation. The molecular mechanism responsible for the phenotype was traced to low expression of N-type calcium channels (alpha1B) and functional alterations of calcium channel currents in neurones projecting to the spinal cord.

Amino Acid Sequence↗
PubMed2003

Presynaptic N-type calcium channels regulate synaptic growth.

Voltage-gated calcium channels couple changes in membrane potential to neuronal functions regulated by calcium, including neurotransmitter release. Here we report that presynaptic N-type calcium channels not only control neurotransmitter release but also regulate synaptic growth at Drosophila neuromuscular junctions. In a screen for behavioral mutants that disrupt synaptic transmission, an allele of the N-type calcium channel locus (Dmca1A) was identified that caused synaptic undergrowth. The underlying molecular defect was identified as a neutralization of a charged residue in the third S4 voltage sensor. RNA interference reduction of N-type calcium channel expression also reduced synaptic growth. Hypomorphic mutations in syntaxin-1A or n-synaptobrevin, which also disrupt neurotransmitter release, did not affect synapse proliferation at the neuromuscular junction, suggesting calcium entry through presynaptic N-type calcium channels, not neurotransmitter release per se, is important for synaptic growth. The reduced synapse proliferation in Dmca1A mutants is not due to increased synapse retraction but instead reflects a role for calcium influx in synaptic growth mechanisms. These results suggest N-type channels participate in synaptic growth through signaling pathways that are distinct from those that mediate neurotransmitter release. Linking presynaptic voltage-gated calcium entry to downstream calcium-sensitive synaptic growth regulators provides an efficient activity-dependent mechanism for modifying synaptic strength.

Alleles↗
PubMed1983

Slow calcium channel blockers and the calcium paradox: comparative studies in the rat with seven drugs.

In studies of the calcium paradox, the isolated perfused rat heart was used to characterize the relationship between myocardial protein leakage and the concentration of calcium antagonist (verapamil and D600) or calcium in the perfusion fluid during a cycle of calcium depletion and repletion. The results indicated a dose-dependency such that protein leakage could be progressively reduced by decreasing the concentration of calcium during calcium repletion and/or by increasing the concentrations of drug. Detailed dose-response studies with seven calcium antagonists (verapamil, D600, nifedipine, terodiline, diltiazem, fendiline and prenylamine) and a calcium concentration of 1.0 mmol/l during a 20 min period of calcium repletion following a 10 min period of calcium depletion revealed complex dose-response characteristics for each drug. In the dose range studied (0 to 40 mumol/l) all drugs with the exception of prenylamine were able to reduce protein leakage by up to 25 to 30% Optimal concentrations for verapamil, nifedipine, D600, diltiazem and terodiline were all between 2.0 and 4.0 mumol/l. With the exception of D600, which provided a constant reduction of protein leakage at all concentrations above this optimum, all drugs exhibited bell-shaped dose-response curves with a loss of efficacy at higher concentrations. Fendiline also had a bell-shaped dose-response curve with 23% as a maximal reduction of leakage; however, the optimal concentration for this drug was 21.0 mumol/l. Additional studies with verapamil revealed that the drug acted during the calcium repletion phase and did not influence events during calcium depletion. Simultaneous use of two drugs, verapamil and nifedipine, at their optimal concentrations failed to improve the reduction in protein leakage over and above that observed with one drug alone.

Animals↗