SEARCH · PubMed Health

Results for “Calcium Channels”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 379 records · Page 21Linked to original sources

PubMed1991

G proteins and calcium channels in myocardium.

Calcium mobilization has been demonstrated to possess functional importance in myocardial excitation-contraction as well as cellular metabolism. So far, much progress has been made to explore the possibility of involvement of guanine nucleotide binding regulatory protein in the opening and closing of calcium channels as well as intracellular second messenger (cyclic adenosine monophosphate and inositol triphosphate) -mediated calcium mobilization, although such work is still in its preliminary stage, the results have proved highly interesting and significant.

Animals↗

PubMed1990

Bimodal operation of the ryanodine-sensitive transducer calcium channel.

Ryanodine binds to the transducer calcium channel complex that links depolarization of the transverse tubule to calcium release from the terminal cisternae during excitation-contraction coupling of skeletal muscle. Ryanodine exerts a bimodal action on the transducer calcium channel complex depending upon membrane potential and concentration. When the transmembrane potential is at resting level (-90 mV inside cell vs outside), low concentrations of ryanodine 10(-10) M to 10(-8) M favor calcium influx from outside which in turn causes calcium release from the terminal cisternae via calcium operated calcium channels. The leak from the terminal cisternae is insufficient to cause contraction but does cause a large increase in aerobic energy utilization by the Ca-ATPase of the sarcoplasmic reticulum. When the transmembrane potential is made more positive (-40 mV) the transducer channel is opened to the terminal cisternae of sarcoplasmic reticulum and is maintained in an open state by ryanodine allowing calcium efflux from the terminal cisternae to the sarcoplasm. At higher concentrations of ryanodine the transducer-calcium channel becomes open to the terminal cisternae and its store of ionized calcium leaks from the terminal cisternae in sufficient quantities to cause a contracture. The ryanodine-sensitive calcium transducer calcium channel operates in a bimodal manner. At low concentrations less than 10(-4) M the ryanodine-sensitive transducer calcium channel is open to the lumen of the T-tubule and allows calcium to flow in and trigger further calcium release. At higher concentrations the ryanodine-sensitive transducer channel opens to allow a calcium efflux from the terminal cisternae in sufficient quantities to cause contracture.

Animals↗

PubMed1987

Identification of the multidrug resistance-related membrane glycoprotein as an acceptor for calcium channel blockers.

A radioactive photoactive dihydropyridine calcium channel blocker, [3H]azidopine, was used to photoaffinity label plasma membranes of multidrug-resistant Chinese hamster lung cells selected for resistance to vincristine (DC-3F/VCRd-5L) or actinomycin D (DC-3F/ADX). Sodium dodecyl sulfate-polyacrylamide gel electrophoretic fluorograms revealed the presence of an intensely radiolabeled 150-180-kDa doublet in the membranes from drug-resistant but not from the drug-sensitive parental (DC-3F) cells. A similar radiolabeled doublet was barely detected in a drug-sensitive partial revertant (DC-3F/ADX-U) cell line. The 150-180-kDa doublet exhibited a specific half-maximal saturable photolabeling at 1.07 X 10(-7) M [3H]azidopine. The dihydropyridine binding specificity was established by competitive blocking of specific photolabeling with nonradioactive azidopine as well as with nonphotoactive calcium channel blockers nimodipine, nitrendipine, and nifedipine. In addition, [3H]azidopine photolabeling was blocked by verapamil and diltiazem but was stimulated by excess prenylamine and bepridil suggesting a cross-specificity for up to four different classes of calcium channel blockers. The 150-180-kDa calcium channel blocker acceptor co-electrophoresed exactly with the 150-180-kDa surface membrane glycoprotein (gp150-180 or P-glycoprotein) Vinca alkaloid acceptor from multidrug-resistant cells and was immunoprecipitated by polyclonal antibody recognizing gp150-180. [3H]Azidopine photolabeling of the 150-180-kDa component in the presence of excess vinblastine was reduced over 90%, confirming the identity or close relationship of the calcium channel blocker acceptor and the gp150-180 Vinca alkaloid acceptor. The [3H]azidopine photolabeling of gp150-180 also was reduced by excess actinomycin D, adriamycin, or colchicine, demonstrating a broad gp150-180 drug recognition capacity. The ability of gp150-180 to recognize multiple natural product cytotoxic drugs as well as calcium channel blockers suggests a direct function for gp150-180 in the multidrug resistance phenomenon and a role in the circumvention of that resistance by calcium channel blockers.

Animals↗

PubMed2003

Modulation and pharmacology of low voltage-activated ("T-Type") calcium channels.

Although T-type calcium channel currents were observed almost 30 years ago, the genes that encode the pore-forming subunits have only been recently reported. When expressed in heterologous systems, three distinct alpha1 subunits (alpha1G (Cav3.1), alpha1H (Car3.2), and alpha1I (Cav3.3)) conduct T-type currents with insert similar but not identical electrophysiological characteristics that. Alpha 1G, alpha 1H, and alpha 1I transcripts are found throughout neural and nonneural tissues, suggesting multiple types of T-type channels (also called low voltage-activated calcium channels (LVAs)) are coexpressed by many tissues. The study of endogenous LVAs has been hampered by a lack of highly selective antagonists that differentiate between LVA subtypes. Furthermore, many pharmacological agents attenuate currents conducted by LVA and high voltage-activated calcium channels (HVAs). At least 15 classes of pharmacological agents affect T-type currents, and the therapeutic use of many of these drugs has implicated LVAs in the etiology of a variety of diseases. Comparison of the responses of recombinant and native LVAs to pharmacological agents and endogenous modulatory molecules will lead to a better understanding of LVAs in normal and diseased cells.

Amino Acid Sequence↗

PubMed2002

Inhibition of transiently expressed low- and high-voltage-activated calcium channels by trivalent metal cations.

Calcium channels are important regulators of neuronal excitability and contribute to transmitter release, calcium dependent gene expression, and oscillatory behavior in many cell types. Under physiological conditions, native low-voltage (T-type)- and high-voltage-activated (HVA) currents are potently inhibited by trivalent cations. However, the presence of multiple calcium channel isoforms has hampered our ability to unequivocally assess the effects of trivalent cations on channel activity. Here, we describe the actions of nine trivalent metal ions on transiently expressed alpha1G (Cav3.1) T-type calcium channels cloned from human brain. In 2 mM external barium solution, yttrium most potently inhibited alpha1G current (IC50 = 28 nM), followed by erbium > gadolinium ~ cerium > holmium > ytterbium > neodymium > lanthanum >> scandium. With the exception of scandium, blocking affinity was loosely correlated with decreasing ionic radius. A detailed characterization of yttrium block revealed a 25-fold decrease in blocking affinity when the external concentration of charge carrier was increased from 2 mM to 20 mM. In 20 mM barium, yttrium also effectively inhibited various types of cloned HVA channels indicating that this ion is a nonselective blocker. For all calcium channels examined, yttrium preferentially inhibited inward over outward current, but block was otherwise voltage independent. In addition to peak current inhibition, P/Q- and L-type channels underwent a unique speeding of the macroscopic time course of inactivation. Whereas peak current block of alpha1A channels was highly sensitive to the external charge carrier concentration, the inactivation effects mediated by yttrium were not, suggesting that the two effects are due to distinct mechanisms. Moreover, the speeding effect was greatly attenuated by manipulations that slowed the inactivation kinetics of the channels. Thus, our evidence suggests that yttrium effects are mediated by two distinct events: peak current block likely occurring by occlusion of the pore, and kinetic speeding arising from yttrium interactions with the channel that alter the state of the inactivation gate.

Calcium Channels↗

PubMed1990

Calcium-calmodulin binding in ischemic rat neurons after calcium channel blocker therapy.

Calcium channel blockers such as nicardipine improve outcome after global cerebral ischemia and may attenuate ischemic neuronal injury by preventing calcium influx and binding to calmodulin. We followed the temporal and regional sequence of neuronal calcium-calmodulin binding in normal rats (n = 6), untreated ischemic rats (n = 15), and ischemic rats treated with 0.05 mg/kg/hr s.c. nicardipine (n = 13). After 30 minutes of four-vessel occlusion, 40-microns brain sections were incubated in an anti-calmodulin antibody specific for calmodulin not bound to calcium and brain protein. Light-microscopic sections were examined immediately after ischemia and after 2 and 24 hours of reperfusion. Extensive staining of unbound calmodulin was seen in all hippocampal regions and in the cortex in normal rats. In untreated ischemic control rats, staining was lost, indicating calcium-calmodulin binding immediately after ischemia in all regions. However, after 24 hours, staining returned to normal in the cortex and dentate, and minimal staining returned in CA1 and CA3. Nicardipine-treated animals had significantly less calcium-calmodulin binding in CA1 and in the dentate after 2 hours of reperfusion. This study demonstrates that in clinically relevant doses nicardipine has a limited effect on calcium-calmodulin binding in selectively vulnerable regions after severe ischemia.

Animals↗

PubMed2000

Determinants of voltage-dependent inactivation affect Mibefradil block of calcium channels.

The voltage gated calcium channel family is a major target for a range of therapeutic drugs. Mibefradil (Ro 40-5967) belongs to a new chemical class of these molecules which differs from other Ca2+ antagonists by its ability to potently block T-type Ca2+ channels. However, this molecule has also been shown to inhibit other Ca2+ channel subtypes. To further analyze the mechanism governing the Ca2+ channel-Mibefradil interaction, we examined the effect of Mibefradil on various recombinant Ca2+ channels expressed in mammalian cells from their cloned cDNAs, using Ca2+ as the permeant ion at physiological concentration. Expression of alpha1A, alpha1C, and alpha1E in tsA 201 cells resulted in Ca2+ currents with functional characteristics closely related to those of their native counterparts. Mibefradil blocked alpha1A and alpha1E with a Kd comparable to that reported for T-type channels, but had a lower affinity (approximately 30-fold) for alpha1C. For each channel, inhibition by Mibefradil was consistent with high-affinity binding to the inactivated state. Modulation of the voltage-dependent inactivation properties by the nature of the coexpressed beta subunit or the alpha1 splice variant altered block at the Mibefradil receptor site. Therefore, we conclude that the tissue and sub-cellular localization of calcium channel subunits as well as their specific associations are essential parameters to understand the in vivo effects of Mibefradil.

Alternative Splicing↗

PubMed2004

Roles of molecular regions in determining differences between voltage dependence of activation of CaV3.1 and CaV1.2 calcium channels.

Voltage-dependent calcium channels are classified into low voltage-activated and high voltage-activated channels. We have investigated the molecular basis for this difference in voltage dependence of activation by constructing chimeras between a low voltage-activated channel (Ca(V)3.1) and a high voltage-activated channel (Ca(V)1.2), focusing on steady-state activation properties. Wild type and chimeras were expressed in oocytes, and two-electrode voltage clamp recordings were made of calcium channel currents. Replacement of domains I, III, or IV of the Ca 3.1 channel with the corresponding domain of Ca(V)1.2 led (V)to high voltage-activated channels; for these constructs the current/voltage (I/V) curves were similar to those for Ca(V)1.2 wild type. However, replacement of domain II gave only a small shift to the right of the I/V curve and modulation of the activation kinetics but did not lead to a high voltage-activating channel with an I/V curve like Ca 1.2. We also investigated the role of the voltage sensor (V)S4 by replacing the S4 segment of Ca(V)3.1 with that of Ca 1.2. For domain I, there was no shift in the I/V curve (V)as compared with Ca(V)3.1, and there were relatively small shifts to the right for domains III and IV. Taken together, these results suggest that domains I, III, and IV (rather than domain II) are apparently critical for channel opening and, therefore, contribute strongly to the difference in voltage dependence of activation between Ca 3.1 and Ca(V)1.2. However, the S4 segments in domains I, (V)III, and IV did not account for this difference in voltage dependence.

Amino Acid Sequence↗

PubMed1986

Mechanisms of calcium channel modulation by beta-adrenergic agents and dihydropyridine calcium agonists.

Cardiac calcium channel activity is markedly increased by beta-adrenergic agents or calcium agonists such as Bay K 8644. The molecular mechanisms underlying these important modulatory effects have been studied with patch clamp techniques by several groups. This paper presents new experiments and reviews published evidence from fluctuation analysis of whole cell calcium current and unitary recordings of single calcium channel activity. Two different factors underlie the enhancement of calcium channel activity seen with beta-stimulation or cyclic AMP: (1) increased availability of calcium channels, expressed in whole cell recordings as an increase in the number of functional channels and in single channel recordings as an increase in the proportion of non-blank sweeps. (2) changes in opening probability, due to alteration of the fast kinetics of channel opening and closing. Both factors contribute to the beta-adrenergic enhancement in frog, rat, and guinea-pig ventricular cells although their quantitative importance is somewhat variable. Unlike beta-adrenergic agents, calcium agonists such as Bay K 8644 promote a mode of channel gating that is characterized by long openings and short closings, seen only rarely in control or with beta-stimulation.

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

PubMed2002

Gamma 1 subunit interactions within the skeletal muscle L-type voltage-gated calcium channels.

Voltage-gated calcium channels mediate excitationcontraction coupling in the skeletal muscle. Their molecular composition, similar to neuronal channels, includes the pore-forming alpha(1) and auxiliary alpha(2)delta, beta, and gamma subunits. The gamma subunits are the least characterized, and their subunit interactions are unclear. The physiological importance of the neuronal gamma is emphasized by epileptic stargazer mice that lack gamma(2). In this study, we examined the molecular basis of interaction between skeletal gamma(1) and the calcium channel. Our data show that the alpha(1)1.1, beta(1a), and alpha(2)delta subunits are still associated in gamma(1) null mice. Reexpression of gamma(1) and gamma(2) showed that gamma(1), but not gamma(2), incorporates into gamma(1) null channels. By using chimeric constructs, we demonstrate that the first half of the gamma(1) subunit, including the first two transmembrane domains, is important for subunit interaction. Interestingly, this chimera also restores calcium conductance in gamma(1) null myotubes, indicating that the domain mediates both subunit interaction and current modulation. To determine the subunit of the channel that interacts with gamma(1), we examined the channel in muscular dysgenesis mice. Cosedimentation experiments showed that gamma(1) and alpha(2)delta are not associated. Moreover, alpha(1)1.1 and gamma(1) subunits form a complex in transiently transfected cells, indicating direct interaction between the gamma(1) and alpha(1)1.1 subunits. Our data demonstrate that the first half of gamma(1) subunit is required for association with the channel through alpha(1)1.1. Because subunit interactions are conserved, these studies have broad implications for gamma heterogeneity, function and subunit association with voltage-gated calcium channels.

Animals↗

PubMed1997

Regulation of melatonin synthesis in rainbow trout (Oncorhyncus mykiss) pineal organs: effects of calcium depletion and calcium channel drugs.

The effects of calcium depletion and of three calcium channel drugs on melatonin synthesis in pineal organs of rainbow trout (Oncorhyncus mykiss) were examined. Dark-induced melatonin synthesis was inhibited by calcium depletion, by treatment with nitrendipine (NTR), an antagonist of the L-type voltage-sensitive calcium channel, and by treatment with omega-Conotoxin GVIA, an antagonist of the N-type voltage-sensitive calcium channel. Bay K 8644, an agonist of the L-type channel, had no significant effect on pineal melatonin synthesis. These data represent evidence that calcium entry into trout pineal photoreceptor cells through voltage-sensitive calcium channels is important in the maintenance of dark-induced melatonin synthesis and that light's inhibitory effect on melatonin synthesis may be mediated by closure of these channels. NTR-induced inhibition of dark-induced melatonin synthesis was abolished when dibutyryl cyclic AMP (db-cAMP) was administered to NTR-treated pineal organs, suggesting that calcium acts upstream of cAMP in regulating melatonin synthesis.

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

PubMed2000

Molecular and functional characterization of a family of rat brain T-type calcium channels.

Voltage-gated calcium channels represent a heterogenous family of calcium-selective channels that can be distinguished by their molecular, electrophysiological, and pharmacological characteristics. We report here the molecular cloning and functional expression of three members of the low voltage-activated calcium channel family from rat brain (alpha(1G), alpha(1H), and alpha(1I)). Northern blot and reverse transcriptase-polymerase chain reaction analyses show alpha(1G), alpha(1H), and alpha(1I) to be expressed throughout the newborn and juvenile rat brain. In contrast, while alpha(1G) and alpha(1H) mRNA are expressed in all regions in adult rat brain, alpha(1I) mRNA expression is restricted to the striatum. Expression of alpha(1G), alpha(1H), and alpha(1I) subunits in HEK293 cells resulted in calcium currents with typical T-type channel characteristics: low voltage activation, negative steady-state inactivation, strongly voltage-dependent activation and inactivation, and slow deactivation. In addition, the direct electrophysiological comparison of alpha(1G), alpha(1H), and alpha(1I) under identical recording conditions also identified unique characteristics including activation and inactivation kinetics and permeability to divalent cations. Simulation of alpha(1G), alpha(1H), and alpha(1I) T-type channels in a thalamic neuron model cell produced unique firing patterns (burst versus tonic) typical of different brain nuclei and suggests that the three channel types make distinct contributions to neuronal physiology.

Alternative Splicing↗

PubMed1988

Calcium channel blockers.

The calcium channel blockers initially were approved for the treatment of classical and variant angina pectoris. Recent studies indicate that these agents also are useful in such diverse conditions as pulmonary and systemic hypertension, hypertrophic cardiomyopathy, arrhythmias, asthma, Raynaud's syndrome, esophageal spasm, myometrial hyperactivity, cerebral arterial spasm, and migraine.

Calcium Channel Blockers↗

PubMedDate not supplied

Calcium channel activation does not increase release of endothelial-derived relaxant factors (EDRF) in rat aorta although tonic release of EDRF may modulate calcium channel activity in smooth muscle.

We investigated whether Ca2+ channel activation by K+ or Bay K 8644 could cause release of endothelium-derived relaxant factor (EDRF) from rat aorta. Bay K 8644 (0.1-100 nM) did not relax rat aorta preparations partially contracted with phenylephrine, although acetylcholine caused large relaxations. Following partial K+-depolarization (12 or 15 mM), Bay K 8644 (10 nM-1 microM) contracted rat aorta preparations directly. Preparations were more sensitive to Bay K 8644 when stripped of the endothelium in 12 mM K+; concentration-effect curves were displaced to the left, and maximum responses were enhanced. In 15 mM K+, there was a leftward shift of the curves without change of maximal responses. However, Bay K 8644 (1 microM), did not increase the guanosine 3',5' cyclic-monophosphate (cGMP) content of rat aorta in the presence of endothelium, which is a function of EDRF release. Representatives (nifedipine, verapamil, cinnarizine) from different calcium antagonist subgroups had differential effects on contractions induced by Bay K 8644, and the effects of verapamil (1 and 10 microM) and lower concentrations of cinnarizine (1 microM) were reduced in the presence of endothelium. We propose that there is a tonic liberation of EDRF in rat aorta, which is unaffected by Ca2+ channel activation and which gives effects similar to a weak hyperpolarization of the smooth muscle cells. Consequently, Ca2+ channel activation and sensitivity to certain calcium-antagonists may be modified.

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

PubMed1986

Membrane activity, antioxidant, antiaggregatory and antihemolytic properties of four calcium channel blockers.

Four calcium channel blockers: nifedipine, fendiline, verapamil and diltiazem have been found to possess different affinity to cytomembranes of platelets and erythrocytes. Nifedipine bound to proteins of the external site of cytomembranes. Verapamil and fendiline possessed affinity to lipids of the cytoplasmic site of the cytomembranes. Diltiazem bound practically neither to erythrocyte nor to platelet membranes. All tested compounds were antioxidants, the strongest being fendiline. Antiaggregatory and antihemolytic properties of tested compounds were roughly correlated with their membrane activity.

Animals↗

PubMed1984

Microcirculatory actions and uses of naturally-occurring (magnesium) and novel synthetic calcium channel blockers.

Synthetic calcium channel blockers (Ca2+ entry blockers or antagonists) have been reported to induce relaxation of smooth muscle which is not thought to be mediated by any specific action(s) on receptor sites. In addition, it has been suggested that Ca2+ channel blockers increases blood flow in a number of organ regions, including mesenteric, femoral, renal, cerebral and coronary vasculatures, via a direct action on vascular tone by inhibiting Ca2+ influx across the vascular smooth muscle membranes. Such information has prompted clinical studies with the use of Ca2+ channel blockers in the treatment of a wide variety of cardiovascular disorders. The questions, to be answered, however, are whether any of the newly-designed channel blockers can actively produce vasodilatation of arterioles and venules in regional microvasculatures, and these synthetic agents are safe and therapeutically effective. In addition, can one design site-specific (e.g., cerebral vs. coronary vasodilator) Ca2+ channel blockers. But, since the body has a natural Ca2+ antagonist, viz., magnesium ions (Mg2+), one must ask whether such divalent cations act as peripheral vasodilators and are effective as therapeutic agents. The studies reviewed herein: compare the effects of several different Ca2+ channel blockers on resistance and capacitance vessels in different regional microvasculatures (i.e., mesenteric, skeletal muscle, pial) within a single species, namely the rat, by high-resolution TV microscopy, and demonstrate the rationale, effects and mechanisms of action of Mg2+ on regional blood vessels. These data show some of the new, novel synthetic Ca2+ channel blockers (i.e., nisoldipine, nitrendipine, nimodipine) can: exert effects on both arterioles and venules in certain vasculatures; be designed to exert a wide range of potencies; and be designed to act selectively at regional microvasculatures. In addition, the data presented are consistent with the hypothesis that Mg2+ exerts a regulatory role in vascular tone, vascular reactivity and vascular resistance. Certain vascular diseases associated with a Mg2+-deficiency appear to be amenable to treatment with Mg2+.

Anesthesia↗

PubMed1988

Regulation of the number of alpha-bungarotoxin binding sites in cultured chick myotubes by a 1,4 dihydropyridine calcium channel antagonist.

Calcium has been suggested as the second messenger link between skeletal muscle activity and AChR gene expression and synthesis. We have compared the concentrations of the Ca2+ channel antagonists D600 and nisoldipine needed both to block Ca2+ uptake into cultured myotubes and to increase AChR expression. The good correspondence between these two measurements and the use of the highly specific Ca2+ channel antagonist nisoldipine strengthens the hypothesis that AChR expression is regulated by levels of intracellular Ca2+.

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

PubMed1993

Functional expression of a rapidly inactivating neuronal calcium channel.

Diverse types of calcium channels in vertebrate neurons are important in linking electrical activity to transmitter release, gene expression and modulation of membrane excitability. Four classes of Ca2+ channels (T, N, L and P-type) have been distinguished on the basis of their electrophysiological and pharmacological properties. Most of the recently cloned Ca2+ channels fit within this functional classification. But one major branch of the Ca2+ channel gene family, including BII (ref. 15) and doe-1 (ref. 16), has not been functionally characterized. We report here the expression of doe-1 and show that it is a high-voltage-activated (HVA) Ca2+ channel that inactivates more rapidly than previously expressed calcium channels. Unlike L-type or P-type channels, doe-1 is not blocked by dihydropyridine antagonists or the peptide toxin omega-Aga-IVA, respectively. In contrast to a previously cloned N-type channel, doe-1 block by omega-CTx-GVIA requires micromolar toxin and is readily reversible. Unlike most HVA channels, doe-1 also shows unusual sensitivity to block by Ni2+. Thus, doe-1 is an HVA Ca2+ channel with novel functional properties. We have identified a Ca2+ channel current in rat cerebellar granule neurons that resembles doe-1 in many kinetic and pharmacological features.

Animals↗