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PubMed1994

Molecular studies of the calcium antagonist binding site on calcium channels.

Currently available calcium antagonists act primarily on L-type calcium channels. Composed of 5 subunits, this ion channel is markedly more complicated than the potassium and sodium channels. Most of the data that have emerged over the past year have concerned the alpha subunit. The secondary structure of this subunit includes 4 repeating motifs; each motif contains 6 membrane-spanning helices, designated S1 through S6. The dihydropyridine (e.g., nifedipine) binding site is most likely situated primarily in motif 4 and the phenylalkylamine (e.g., verapamil) binding site is on motif 4 in an intracellular region. The benzothiazepine (e.g., diltiazem) binding site is also located on the alpha 1 subunit, but its precise location has not been determined. The transmembrane helices S5 and S6 of each motif have been proposed as the "wall" of the actual ion channel.

Binding Sites↗
PubMed1983

The effects of calcium channel inhibitors and other procedures affecting calcium translocation on drug-induced rhythmic contractions in the rat vas deferens.

In the rat isolated vas deferens, methoxamine 8.1 microM produced an initial phasic response that declined towards baseline and was followed by rhythmic contractions that continued until wash-out. These responses were predominant in the epididymal half. BaCl2 1 mM produced a similar type of response which was not mediated by noradrenaline release or activation of alpha-adrenoceptors. The barium responses were similar in the epididymal and prostatic halves. Incubation in nominally Ca2+-free solution caused abolition or near abolition of rhythmic contractions produced by barium or methoxamine. The initial phasic response to methoxamine was abolished in Ca2+-free solution, whereas that produced by barium persisted. Rhythmic contractions produced by methoxamine or barium were inhibited by Mg2+ (2.4-20 mM) and by La3+ (1-5 mM). Mg2+ had selectivity for inhibition of the frequency of methoxamine- but not barium-induced rhythmic contractions. Despite their dependence on [Ca2+]o, barium- and methoxamine-induced rhythmic contractions were resistant to inhibition by calcium channel inhibitors. Verapamil, nifedipine and flunarazine inhibited the amplitude of rhythmic contractions more readily than the frequency (methoxamine IC50 for verapamil: amplitude = 29.8 +/- 5.40 microM, n = 6, frequency = 96.7 +/- 31.0 microM, n = 5, for nifedipine: amplitude = 2.42 +/- 0.34 microM, n = 7, frequency = 3.24 +/- 0.75 microM, n = 7, and for flunarizine: amplitude = 15.9 +/- 5.95 microM, n = 7, frequency = 153 +/- 28.6 microM, n = 7). There was no differentiation between inhibition of methoxamine and barium-induced responses. Like Mg2+, methoxyverapamil selectively inhibited the frequency of methoxamine-induced contractions (IC50: amplitude = 16.8 +/- 2.86 microM, n = 5, frequency = 2.07 +/- 0.81 microM, n = 5) but not barium-induced contractions (IC50: amplitude = 13.9 +/- 1.95 microM, n = 5, frequency = 48.5 +/- 8.98 microM, n = 5). Diazoxide (43.3-2167 microM) and nitroprusside (3.36-6712 microM) had only a small effect on barium contractions, but produced a dose-related reduction in the amplitude of methoxamine-induced responses. Diazoxide and nitroprusside caused methoxamine contractions to occur in groups, although they had no effect on their overall frequency. It is concluded that barium- and methoxamine-induced rhythmic contractions in the rat vas deferens are mediated by the entry of [Ca2+]o via membrane calcium channels that have a lower affinity (10-100 X) for calcium channel inhibitors than those mediating the KCl response. Channels activated by methoxamine are concentrated in the epididymal half, whereas those opened by barium are evenly distributed. However, although responses to methoxamine and barium are similar in form, differences in the effects of some of the drugs tested, together with the results of previous studies, indicate that they produce contractions by different mechanisms.

Animals↗
PubMed1993

[Reversal by the calcium ion of the pain threshold elevated by calcium channel blockers].

We investigated calcium ion effects on pain thresholds by iontophoresis in healthy adult volunteers. The pain thresholds were measured by the pain thermometer to evaluate the effect of iontophoresis. At first, one of calcium channel blockers (nicardipine, verapamil or diltiazem) was administered by iontophoresis with 1.0 mA for 10 minutes. Then, next to calcium channel blockers, calcium chloride or saline was locally administered after the elevation of pain threshold had been recognized and the pain threshold had been measured again. Calcium ion decreased the elevation of pain threshold significantly, but saline had no effect. These results suggest that not only sodium channel but also calcium channel influences pain mechanism during iontophoresis.

Adult↗
PubMed1997

Effects of aranidipine, a novel calcium channel blocker, on mechanical responses of the isolated rat portal vein: comparison with typical calcium channel blockers and potassium channel openers.

We investigated the effects of aranidipine, a dihydropyridine-type Ca2+ channel blocker, on contractile responses to KCl and spontaneous contractions in isolated rat portal veins in comparison with those of the Ca2+ channel blockers, nifedipine, nicardipine, nitrendipine, diltiazem, and verapamil, and of the K+ channel openers, cromakalim and nicorandil. All the Ca2+ channel blockers concentration-dependently inhibited contractions induced by KCl. Interestingly, aranidipine was more potent against the low K+ (20 mM)-induced contraction than the high K+ (80 mM)-induced contraction, whereas the other Ca2+ channel blockers were equally potent against contractions induced by either concentration of KCl. Cromakalim and nicorandil were effective only on the low K(+)-induced contraction. In addition, all the Ca2+ channel blockers and the K+ channel openers tested inhibited the amplitude of spontaneous contractions of isolated rat portal vein. Tetraethylammonium (TEA), a classic K+ channel blocker, significantly attenuated the effect of aranidipine but not of other Ca2+ channel blockers on the spontaneous contractions. The cromakalim-induced inhibition of spontaneous contractions was antagonized by TEA. Thus aranidipine was found to be different from the typical Ca2+ channel blockers and in part similar to the K+ channel openers in inhibiting mechanical responses of isolated rat portal vein, suggesting that activation of K+ channels may in part in part be involved in the aranidipine-induced vasodilation.

Animals↗
PubMed1996

Antiarrhythmic and anti-ischemic properties of calcium-channel antagonists.

The calcium-channel blockers are an ever-enlarging, heterogeneous group of drugs with widely variable effects on myocardium, sinoatrial and atrioventricular nodal function and conduction, peripheral blood vessels, and coronary circulation. Since the development and characterization of calcium-channel antagonists in the 1960s, these agents have become increasingly important in the treatment of many cardiovascular diseases. Nine calcium-channel blockers-nifedipine, nicardipine, amlodipine, felodipine, isradipine, nimodipine, diltiazem, verapamil, and bepridil-are all approved for use in the United States. Each major category has its own unique physiologic features. These drugs are extremely useful in the management of cardiac arrhythmias (particularly supraventricular arrhythmias) and/or ischemia. As future generations of calcium-channel blockers are developed with greater vasoselectivity, less negative inotropic effects, and reduced tendency to activate the renin-angiotensin system, their indications for use will continue to grow.

Angioplasty, Balloon, Coronary↗
PubMed1989

Nonmodal gating of cardiac calcium channels as revealed by dihydropyridines.

The hypothesis that dihydropyridine (DHP)-sensitive calcium channels have three distinct modes of gating has been examined. The major prediction is that the relative frequencies among modes depend on DHP concentration while the kinetics within a mode do not. We tested this by studying whole-cell and single-channel calcium currents in neonatal rat and adult guinea pig cardiac myocytes in different concentrations of several DHPs. In the absence of DHPs calcium currents declined with time but the kinetics, which are the focus of this study, were unchanged. Open-time frequency distributions had insignificant numbers of prolonged openings and were well fit by single tau's. Agonist DHP stereoisomers produced concentration-dependent changes in whole-cell tail current tau's. The frequency distribution of single calcium channel current open times became biexponential and the tau's were concentration dependent. The average number of openings per trace of channels with customary open times increased with increases in DHP concentration. Latencies to first opening for the customary openings and for prolonged openings were shorter in the presence of DHPs. A second larger conductance is another important feature of DHP-bound single calcium channels. Thus DHPs not only caused prolonged openings; they produced numerous changes in the kinetics of customary openings and increased channel conductance. It follows that these effects of DHPs do not support the hypothesis of modal gating of calcium channels. The mode model is not the only model excluded by the results; models in which DHPs are allowed to act only or mainly on open states are excluded, as are models in which the effects are restricted to inactivated states. We suggest a different type of model in which cooperative binding of DHPs at two sites produces the essential changes in kinetics and conductance.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Further characterization of phasic calcium influx in rat cerebrocortical synaptosomes: inferences regarding calcium channel type(s) in nerve endings.

Under conditions minimizing the contribution of Na+/Ca2+ exchange to calcium entry in synaptosomes, the K+ depolarization-dependent calcium influx (JCa) is a single exponential function of time. JCa activates and slowly inactivates at membrane potentials positive to -50 mV, a result indicating the involvement of moderate voltage-activating, slowly inactivating calcium channels. Calcium channels in synaptosomes are characterized by stronger sensitivity to blockage by Cd2+ than Co2+, insensitivity to dihydropyridine calcium antagonists or the agonist Bay K 8644, and weak, partial sensitivity to the peptide toxin omega-conotoxin GVIA. These characteristics suggest that voltage-sensitive calcium channels in rat cerebrocortical synaptosomes are dissimilar from the somatic T, N, or L channel types. JCa is not affected by treatment of synaptosomes with the adenylate cyclase activator forskolin, the membrane permeant dibutyryl-cyclic AMP, or the kinase C activator phorbol 12-myristate 13-acetate diester, results suggesting that calcium channels in synaptosomes are not directly modulated by protein kinase A- or C-mediated phosphorylation.

Animals↗
PubMed2000

Epithelial calcium channel: gate-keeper of active calcium reabsorption.

The epithelial calcium channel present in the apical membrane of 1,25-dihydroxyvitamin D3-responsive nephron segments represents the first member of a new family of calcium channels. This review covers the distinctive properties of this highly calcium-selective channel and highlights the implications for our understanding of the process of calcium reabsorption.

Amino Acid Sequence↗
PubMed2006

The effect of protein dielectric coefficient on the ionic selectivity of a calcium channel.

Calcium-selective ion channels are known to have carboxylate-rich selectivity filters, a common motif that is primarily responsible for their high Ca(2+) affinity. Different Ca(2+) affinities ranging from micromolar (the L-type Ca channel) to millimolar (the ryanodine receptor channel) are closely related to the different physiological functions of these channels. To understand the physical mechanism for this range of affinities given similar amino acids in their selectivity filters, we use grand canonical Monte Carlo simulations to assess the binding of monovalent and divalent ions in the selectivity filter of a model Ca channel. We use a reduced model where the electolyte is modeled by hard-sphere ions embedded in a continuum dielectric solvent, while the interior of protein surrounding the channel is allowed to have a dielectric coefficient different from that of the electrolyte. The induced charges that appear on the protein/lumen interface are calculated by the induced charge computation method [Boda et al., Phys. Rev. E 69, 046702 (2004)]. It is shown that decreasing the dielectric coefficient of the protein attracts more cations into the pore because the protein's carboxyl groups induce negative charges on the dielectric boundary. As the density of the hard-sphere ions increases in the filter, Ca(2+) is absorbed into the filter with higher probability than Na(+) because Ca(2+) provides twice the charge to neutralize the negative charge of the pore (both structural carboxylate oxygens and induced charges) than Na(+) while occupying about the same space (the charge/space competition mechanism). As a result, Ca(2+) affinity is improved an order of magnitude by decreasing the protein dielectric coefficient from 80 to 5. Our results indicate that adjusting the dielectric properties of the protein surrounding the permeation pathway is a possible way for evolution to regulate the Ca(2+) affinity of the common four-carboxylate motif.

Calcium↗
PubMed2002

Effects of arecoline on calcium channel currents and caffeine-induced calcium release in isolated single ventricular myocyte of guinea pig.

The effects of Arecoline (Are) on calcium mobilization were investigated. In isolated single ventricular myocyte of guinea pig, patch clamp whole cell recording techniques were used to record the current of L-type calcium channel and cytosolic Ca2+ level ([Ca2+]i) labeled with fluorescence probe Fluo-3/AM was measured under a laser scanning confocal microscope. Results revealed that Are (3-100 mumol/L) could inhibit L-type calcium current in a concentration-dependent manner and the value of IC50 was 33.73 mumol/L (n = 5). In the absence of extracellular calcium, the resting levels of [Ca2+]i was not affected by Are (n = 6, P > 0.05), but pretreatment with Are (30 mumol/L) could significantly inhibit the [Ca2+]i elevation induced by caffeine (10 mmol/L, n = 6, P < 0.01). It was concluded that Are could inhibit not only calcium influx through L-type calcium channel but also calcium release from sarcoplasmic reticulum.

Animals↗
PubMed1986

Fast and slow gating behaviour of single calcium channels in cardiac cells. Relation to activation and inactivation of calcium-channel current.

The Ca-channel gating behaviour during steady and stepwise depolarization was examined in recordings of single Ca-channel activity from cell-attached membrane patches of single ventricular cells isolated enzymatically from hearts of adult guinea pigs. The single-channel recordings were performed by means of the improved patch-clamp technique (Hamill et al. 1981) with 90 mM Ba in the pipettes. Upon step depolarization, two types of current records were regularly observed in the ensembles: (1) traces with Ca-channel activity (in the form of closely-spaced brief pulses of inward current with a unitary amplitude) of various length, and (2) blank sweeps without any detectable single-channel opening. The records with Ca-channel activity show a distinct tendency for openings to occur towards the beginning of the clamp pulse, followed by long periods of silence. The blank sweeps seem to reflect a condition or conditions where the Ca channel is unavailable for opening. The corresponding ensemble mean current I(t) displayed a rapid rising phase to its peak followed by a slow decay. During steady depolarization, kinetic analysis of the distributions of all open and shut lifetimes revealed a monoexponential probability density distribution function of all open times. By contrast, more than two exponential terms were required for an accurate description of the frequency distribution of all shut lifetimes. Corresponding to the two well-separated fast closed time components, individual Ca-channel openings were grouped into bursts of openings. The bursting behaviour reflected fast gating transitions and was related to the fluctuations of the Ca channel between two short-lived closed states and one open state. This fast gating was terminated by the entrance of the Ca channel into at least one long-lived closed state, exit from which was slow in comparison to the rapid cycling. As consequence, bursts of openings were further grouped together in clusters of bursts, the cluster behaviour being related to slow gating transitions in the kinetics of the Ca channel. The biphasic frequency distribution of the first latencies (resulting from the transit through the two short-lived shut states, before the open state is entered) superimposed on the first time derivative of the rising phase of the ensemble mean current, I(t), upon step depolarization. The time constant of the monoexponential distribution function of all cluster lifetimes matched the declining phase of I(t) during maintained depolarization.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Calcium channel blockers and cardiac surgery.

Calcium channel blockers have an important role in the pharmacotherapy of cardiovascular disorders. These agents act by inhibiting the slow inward current into excitable cells, exert direct negative inotropic, chronotropic, and dromotropic activity, and are potent vasodilators. These direct effects are modified by reflex autonomic stimulation and by pathologic states. Serious adverse effects of the calcium channel blockers are most frequently observed in patients with ventricular dysfunction, conduction system disease, or concomitant beta blockade. Calcium channel blockers are indicated in the treatment of angina pectoris, supraventricular arrhythmias, and hypertension. The use of these agents in patients with hypertrophic cardiomyopathy, congestive heart failure, and pulmonary hypertension is investigational. The calcium channel blockers are gaining increased importance in the management of patients undergoing cardiac surgery. Verapamil is indicated for the treatment of post-cardiac-surgical atrial flutter and fibrillation; however, the calcium antagonists are not effective as prophylaxis against postoperative supraventricular arrhythmias. Laboratory studies have shown that drug interactions exist between calcium channel blockers and inhalational anesthetics and nondepolarizing neuromuscular blocking agents; clinical studies have demonstrated that these interactions are rarely significant. Perioperative coronary spasm can be effectively treated with the calcium channel blockers. The timing of calcium antagonist withdrawal prior to surgery is controversial, but continuation of therapy until surgery is usually safe. The clinical significance of platelet function inhibition by the calcium antagonists is unknown. Protection of ischemic myocardium by calcium channel blockers has been demonstrated. Important interactions between the calcium antagonists, hypothermia, and the ionic constituents of cardioplegia require further study before the role of these agents as adjuncts to clinical cardioplegia is defined. Expanded indications and the introduction of new calcium channel blockers will result in increased use of these agents in the future.

Calcium Channel Blockers↗
PubMed2002

Tyrosine kinases act directly on the alpha1 subunit to modulate Ca(v)2.2 calcium channels.

Voltage-operated calcium channels are modulated by tyrosine kinases in different cell types. In this study, I(Ba) was measured by the whole cell voltage-clamp technique in single COS-7 cells overexpressing the Ca(v)2.2 calcium channels encoding N-type currents. Bath application of genistein, a nonselective PTK inhibitor (50-300 microM), concentration-dependently inhibited calcium channel currents, whereas the inactive structural analogue, daidzein, was without effect over the same concentration range. Similarly, PP1, a src family-selective tyrosine kinase inhibitor, inhibited I(Ba) in a concentration-dependent manner (500 nM-5 microM) over a range of test potentials. Expression of the Ca(v)2.2alpha1 (alpha(1B)) subunit alone gave rise to functional channels, and genistein (100 microM) also inhibited currents elicited by the alpha(1B) subunit alone. These results indicate that tyrosine kinase inhibitors are likely to inhibit Ca(v)2.2 calcium channels via an action on the pore-forming alpha(1) subunit and suggest that an endogenous member of the Src family may play a physiological role in modulating these channels.

Animals↗
PubMed1995

Critical amino acids responsible for conferring calcium channel characteristics are located on the surface and around beta-turn potentials of channel proteins.

Calcium ion is thought to be one of the initial signals in the process of synaptic modification. Various reports have described that the critical amino acids responsible for determining calcium permeability of ion channels are glutamic acid, glutamine, arginine, and asparagine. By using a computational method (MacPROT) distinguishing transmembrane, globular, and surface sequences of proteins, the present work predicts that the critical amino acids exist within surface regions of the proteins. Furthermore, occurrence of beta-turn probabilities can be predicted around these critical residues by the protein conformational prediction method of Chou and Fasman. The results suggest that the critical amino acids exist at hydrophilic spaces or canals of membranous channel proteins and that the redirection potential of the protein chain induced by the turn structures provides the conformational change requisite for the ion selectivity and gating (opening/closing) of the channels.

Amino Acid Sequence↗
PubMed1996

A novel hydrophobic omega-conotoxin blocks molluscan dihydropyridine-sensitive calcium channels.

A novel calcium channel blocking peptide designated omega-conotoxin-Tx VII has been characterized from the venom of the molluscivorous snail Conus textile. The amino acid sequence (CKQADEPCDVFSLDCCTGICLGVCMW) reveals the characteristic cysteine framework of omega-conotoxins, but it is extremely hydrophobic for this pharmacological class of peptides and further unusual in its net negative charge (-3). It is further striking that the sequence of TxVII, a calcium current blocker, is 58% identical to that of delta-conotoxin-TxVIA, which targets sodium channels. TxVII effects were examined in the caudodorsal cell (CDC) neurons from the mollusc Lymnaea stagnalis. The toxin has no significant effect on sodium or potassium currents in these cells, but it clearly blocks the calcium currents. TxVII most prominently blocks the slowly inactivating, dihydropyridine- (DHP-) sensitive current in CDCs, while blockade of the rapidly inactivating current is less efficient. This novel omega-conotoxin is apparently targeted to DHP-sensitive calcium channels and thereby provides a lead for future design of selective conopeptide probes for L-type channels.

Amino Acid Sequence↗
PubMed2003

Beta1-integrins co-localize with Na, K-ATPase, epithelial sodium channels (ENaC) and voltage activated calcium channels (VACC) in mechanoreceptor complexes of mouse limb-bud chondrocytes.

Interactions between chondrocytes and their extracellular matrix are partly mediated by beta1-integrin receptors. Recent studies have shown that beta1-integrins co-localize with a variety of cytoskeletal complexes, signaling proteins and growth factor receptors. Since mechanosensitive ion channels and integrins have been proposed to participate in skeletal mechanotransduction, in this study, we investigated the possible co-localization of beta1-integrins with two ion channels and a P-type ATPase in mouse limb-bud chondrocytes. The alpha subunits of Na, K-ATPase, the epithelial sodium channel (ENaC) and the voltage activated calcium channel (VACC) were immunostained in organoid cultures derived from limb-buds of 12-day-old mice using well-characterized antibodies. Indirect immunofluorescence revealed abundant expression of beta1-integrins and each of the selected systems in limb-bud chondrocytes. Two-fluorochrome immunostaining demonstrated that beta1-integrin, Na, K-ATPase, ENaC and VACC co-localize in chondrocytes. Co-imunoprecipitation experiments revealed co-localization and association of integrins with ENaC, VACC and Na, K-ATPase. Cellular responses and signaling cascades initiated by the influx of calcium or sodium through putative mechanosensitive channels may be regulated more effectively if such channels were organized around integrins with receptors, kinases and cytoskeletal complexes clustered about them. The close proximity of ATPase ion pumps such as Na, K-ATPase to chondrocyte mechanoreceptor complexes could facilitate rapid homeostatic responses to the ionic perturbations brought about by activation of mechanically gated cation channels and efficiently regulate the intracellular milieu of chondrocytes.

Amino Acid Sequence↗
PubMed1996

[Value of calcium channel blockers in the prevention of ventricular fibrillation of ischemic etiology: experimental arguments].

The prevention of ventricular fibrillation raises a special problem when related to myocardial ischaemia, since class I antiarrhythmic drugs are then ineffective and may even behave as profibrillatory agents: the usual antifibrillatory properties of these drugs which are inhibitors of sodium channel, activated at high potentials, disappear with the disappearance of the role of sodium channel caused by ischaemic depolarization. Calcium channel then replacing sodium channel, calcium channel inhibitors should tend to prevent ischaemic ventricular fibrillation. Therefore, vulnerability to ventricular fibrillation was assessed in open-chest pigs by the threshold for fibrillation electrically induced with impulses of 100 ms duration at the rate of 180 beats/min. Ischaemia was produced by total occlusion of the left anterior descending coronary artery near its origin. Electrical fibrillation threshold was measured at the end of ischaemic period of increasing duration (30, 60, 120, 180, 240, 360 s) under control conditions and after i.v. administration of verapamil (50 micrograms/kg loading dose and 2 micrograms/kg/min infusion). Unaffected by verapamil when coronary circulation was normal, fibrillation threshold was raised by the drug when lowered by ischaemia, increasingly with the prolongation of ischaemia responsible for depolarization of the fibres, up to 500%. The rise of fibrillation threshold resulted in a delay in the triggering of fibrillation which occurs when the fibrillation threshold (6-8 mA) falls down to the pacing threshold (0.3-0.4 mA). These experiments tend to confirm the positive results recently obtained in man with verapamil in the prevention of postinfarction sudden death, provided that myocardial contractility is not too much adversely affected. But, in these experiments, left ventricular dP/dt max was not reduced by more than 15%, even just after the loading dose and returned to its control values within a few minutes.

Animals↗