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PubMed2006

Differential regulation of calcium channel coding genes by prolonged depolarization.

Calcium channels must be subjected to a very precise regulation in order to preserve cell function and viability. Voltage gated calcium channels (VGCC) represent the main pathway for calcium entry in excitable cells. This explains why depolarization induces a rapid-onset and short-term inactivation of calcium currents. Contrarily to this well-documented mechanism to maintain calcium below toxic levels, the regulatory pathways inducing longer-lasting changes and cell surface expression of functional calcium channels are largely unknown. Since calcium is a main player in the activity-dependent regulation of many genes, we hypothesize that calcium channel coding genes could be also subjected to activity-dependent regulation. We have used prolonged depolarization to analyze the effects of sustained intracellular calcium elevation on the mRNAs coding for the different alpha(1) pore-forming subunits of the calcium channels expressed in chromaffin cells. Our findings reveal that persistent depolarization is accompanied by a prolonged intracellular calcium elevation and reduction of calcium current. This calcium current inhibition could be mediated, at least partially, by the downregulation of the mRNAs coding for several alpha(1) subunits. Thus, we show here that depolarization inhibits the expression of Ca(V)1.1, Ca(V)1.2, Ca(V)1.3, Ca(V)2.2 and Ca(V)2.3 mRNAs, while the Ca(V)2.1 mRNA remains unmodified. Moreover, such downregulation of channels depends on calcium entry through the L-type calcium channel, as both mRNA and calcium current changes induced by depolarization are abrogated by L-type channel specific blockers.

Animals↗

PubMed2003

Neurotransmitter modulation of neuronal calcium channels.

There are many different calcium channels expressed in the mammalian nervous system, but N-type and P/Q-type calcium channels appear to dominate the presynaptic terminals of central and peripheral neurons. The neurotransmitter-induced modulation of these channels can result in alteration of synaptic transmission. This review highlights the mechanisms by which neurotransmitters affect the activity of N-type and P/Q-type calcium channels. The inhibition of these channels by voltage-dependent and voltage-independent mechanisms is emphasized because of the wealth of information available on the intracellular mediators and on the effect of these pathways on the single-channel gating.

Action Potentials↗

PubMed2005

[Calcium channel blocker and cardiac hypertrophy].

Calcium channel blockers are commonly treated to the patients with hypertension. Epidemiological studies suggest that cardiac hypertrophy is an independent risk factor for cardiac morbidity and mortality from cardiovascular disease. Long-acting calcium channel blockers, but not short-acting calcium channel blockers had moderately beneficial and statistically indistinguishable effects on regression of LV hypertrophy. Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2004) recommended to treat A II receptor blockers, ACE inhibitors or calcium channel blockers against the hypertensive patients with cardiac hypertrophy. Further studies will be necessary to elucidate the detailed molecular mechanism how calcium channel blockers reduce cardiac hypertrophy.

Animals↗

PubMed1998

Mechanism of auxiliary subunit modulation of neuronal alpha1E calcium channels.

Voltage-gated calcium channels are composed of a main pore-forming alpha1 moiety, and one or more auxiliary subunits (beta, alpha2 delta) that modulate channel properties. Because modulatory properties may vary greatly with different channels, expression systems, and protocols, it is advantageous to study subunit regulation with a uniform experimental strategy. Here, in HEK 293 cells, we examine the expression and activation gating of alpha1E calcium channels in combination with a beta (beta1-beta4) and/or the alpha2 delta subunit, exploiting both ionic- and gating-current measurements. Furthermore, to explore whether more than one auxiliary subunit can concomitantly specify gating properties, we investigate the effects of cotransfecting alpha2delta with beta subunits, of transfecting two different beta subunits simultaneously, and of COOH-terminal truncation of alpha1E to remove a second beta binding site. The main results are as follows. (a) The alpha2delta and beta subunits modulate alpha1E in fundamentally different ways. The sole effect of alpha2 delta is to increase current density by elevating channel density. By contrast, though beta subunits also increase functional channel number, they also enhance maximum open probability (Gmax/Qmax) and hyperpolarize the voltage dependence of ionic-current activation and gating-charge movement, all without discernible effect on activation kinetics. Different beta isoforms produce nearly indistinguishable effects on activation. However, beta subunits produced clear, isoform-specific effects on inactivation properties. (b) All the beta subunit effects can be explained by a gating model in which subunits act only on weakly voltage-dependent steps near the open state. (c) We find no clear evidence for simultaneous modulation by two different beta subunits. (d) The modulatory features found here for alpha1E do not generalize uniformly to other alpha1 channel types, as alpha1C activation gating shows marked beta isoform dependence that is absent for alpha1E. Together, these results help to establish a more comprehensive picture of auxiliary-subunit regulation of alpha1E calcium channels.

Binding Sites↗

PubMed1996

[Calcium channel blockers in pregnancy].

Calcium channel blockers are used more and more in pregnancy. No teratogenic effect has been observed in humans despite the lack of adequate studies. The use of calcium channel blockers in premature labor and in arterial hypertension may be recommended. In premature labor, maternal tolerance is better than that of beta adrenergic drugs. In hypertensive disorders of pregnancy, current data indicate that calcium channel blockers may be a good second line medication. Acute lowering of maternal blood pressure (by sublingual or intravenous use) may however induce fetal distress.

Antihypertensive Agents↗

PubMed1994

Single-channel properties of high- and low-voltage-activated calcium channels in rat pituitary melanotropic cells.

1. Single-channel properties of voltage-dependent calcium channels were investigated in rat melanotropes in short-term primary culture. Unitary currents were resolved using the cell-attached configuration. 2. Depolarizations higher than -50 mV activated a population of 8.1-pS calcium channels [low-voltage activated (LVA)]. The LVA channel ensembles displayed a monoexponential time course of inactivation and a sigmoidal time course of activation fitted best by an m2h Hodgkin-Huxley-type model. Microscopic kinetic analysis suggested that at least one open state, two closed states, and one inactivated state are involved in channel gating. 3. At potentials positive to -20 mV a second class of calcium channels was activated with a conductance of 24.7 pS [high-voltage activated (HVA)]. HVA channels display different gating modes. Gating with high open probability (mode 2) and low open probability (mode 1) as well as blank traces (mode 0) are observed. The HVA channels were heterogeneous with respect to their inactivation properties. Ensembles that decayed entirely during a 300-ms test pulse as well as nondecaying ensembles were observed. Both HVA channel subtypes displayed sigmoidal activation, which was fitted by an m2 model. Microscopic kinetic analysis suggested that at least one open state and two closed states are involved in mode two gating of both HVA channel subtypes. 4. Depolarizing prepulses did not recruit or facilitate calcium channel activity in response to a test pulse, but inactivating HVA channel activity was strongly reduced. Depolarizing prepulses (+50 mV) did not affect the probability of opening of the noninactivating HVA channel. 5. The voltage dependence and kinetics of the LVA as well as both HVA channels are in good agreement with previously published data on the properties of the various calcium current components derived from whole-cell recordings of rat melanotropes. The data suggest that a T-type as well as two L-type channels (an inactivating and noninactivating channel) underlie the calcium current in these cells.

Animals↗

PubMed2003

Human skeletal muscle calcium channel alpha1S is expressed in the basal ganglia: distinctive expression pattern among L-type Ca2+ channels.

Voltage-gated calcium channels (VGCCs) are essential molecules for neuronal function. VGCCs consist of five subunits, alpha1, alpha2, beta, gamma, and delta. Among the ten subtypes of the alpha1 subunit (alpha1A-I and S), expression of alpha1S was previously believed to be restricted to the skeletal muscle. We report here, however, that alpha1S is also expressed in human and rat central nervous system. First, we performed PCR screening for VGCC alpha1 subunits in human nervous system using degenerate primers, and identified alpha1S as well as all the eight alpha1 subunits with previously described expression. Intriguingly, alpha1S was selectively localized to the basal ganglia, particularly the caudate nucleus. In situ hybridization showed that alpha1S was expressed in medium-sized caudate neurons. Quantitative analysis using real time RT-PCR revealed a distinct pattern of alpha1S expression among L-type calcium channels. Furthermore, RT-PCR using laser-mediated manipulation of single cells suggested that human alpha1S was coexpressed with ryanodine receptors (RYRs) in GABAergic neurons. Our results suggest the potential relevance of alpha1S to dopaminergic signal transduction and calcium-induced calcium release in caudate neurons.

Animals↗

PubMed1991

Enzymatic gating of voltage-activated calcium channels.

The model of calcium-channel gating described above, although almost certainly too simple, suggests a direct role for protein kinases and phosphatases in determining the kinetics of calcium channel gating on a subsecond time scale. In addition, it provides a unique perspective for understanding studies of calcium channel gating under widely different metabolic and pharmacological conditions. Although many of these effects may be specific to the dihydropyridine-sensitive or L-type calcium channel, they give an indication of the range of possibilities for integrating calcium-channel activity with cellular biochemistry.

Animals↗

PubMed1994

Effects of diltiazem in convulsive states differ from those previously reported for dihydropyridine calcium channel antagonists.

Unlike the dihydropyridine calcium channel antagonists studied previously, the benzothiazepine calcium channel antagonist, diltiazem, increased the incidence of convulsions caused by bicuculline, N-methyl-DL-aspartate or 4-aminopyridine. However, the latencies to convulsions were also increased. Diltiazem increased the ratings of convulsive behaviour on handling after intraperitoneal administration of bicuculline, or pentylenetetrazol and after the calcium channel activator, Bay K 8644, administered ICV. When the binding of the dihydropyridine, [3H]-nitrendipine in the CNS was measured in vivo, this was increased by diltiazem. This compound therefore showed a different pattern of interaction with convulsant drugs then that previously demonstrated for other calcium channel antagonists, appearing to possess both pro- and anticonvulsant actions, and a different pattern of interaction with the dihydropyridine receptor complex.

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

PubMed2004

Different effects of L-type and L+N-type calcium channel blockers on hamster cheek pouch venules.

Dihydropyridine calcium channel blockers are not uniform in terms of their action on calcium channel. L-type calcium channel blockers dilate the resistance arterioles. Cilnidipine is a dihydropyridine calcium channel blocker that also acts on N-type calcium channels, and may dilate venules through its effect on the sympathetic receptor. The influence of an L-type calcium channel blocker (nifedipine) or this L+N type blocker at 10(-7) mol to 10(-4) mol on venular diameter was examined by superfusion of male Syrian hamster cheek pouches. Nifedipine dose dependently dilated the arterioles alone, whereas cilnidipine dilated both arterioles and venules. Application of 10(-7) mol omega conotoxin, an inhibitor of N-type channels, after nifedipine led to significant dilation of venules, while it had no influence when administered after cilnidipine. These findings indicate that the effects of calcium channel blockers on the venules differ according to the action on N-type calcium channels, and that cilnidipine (an L+N type calcium channel blocker) dilates venules through its additional action on N-type channels.

Animals↗

PubMed1996

Do calcium channel blockers increase the risk of cancer?

Calcium channel blockers can block calcium signals that trigger cell differentiation and apoptosis, which are important mechanisms of cancer growth regulation. To ascertain whether calcium channel blocker use was associated with an increased risk of cancer, 750 hypertensive persons age > or = 71 years, with no history of cancer at baseline, were followed from 1988 through 1992. The patients were using either beta-blockers, angiotensin converting enzyme inhibitors or calcium channel blockers (verapamil, nifedipine, and diltiazem; mainly of the short-acting variety). Compared to beta-blockers (n = 424, 28 events), after adjusting for age, gender, race, smoking, body mass index, and number of hospital admissions not related with cancer, the relative risks of cancer (95% confidence interval) for angiotensin converting enzyme inhibitors (n = 124, 6 events) and calcium channel blockers (n = 202, 27 events) were 0.73 (0.30 to 1.78) and 2.02 (1.16 to 3.54), respectively. These findings indicate that calcium channel blocker therapy might increase the risk of cancer. New data are needed in patients using modern calcium channel blocker agents with more gradual absorption. This report should encourage further study of cancer outcomes in elderly patients who are vulnerable to cancer and who are receiving calcium channel blockers.

Adrenergic beta-Antagonists↗

PubMed2000

Conserved smooth muscle contractility and blood pressure increase in response to high-salt diet in mice lacking the beta3 subunit of the voltage-dependent calcium channel.

Voltage-dependent calcium channels are crucially important for calcium influx and the following smooth muscle contraction. Beta subunits of these channels are known to modify calcium currents through pore-forming alpha subunits. Among the four reported independent beta subunits, the beta3 subunit is expressed in smooth muscle cells and thought to compose L-type calcium channels in the tissue. To determine the role of the beta3 subunit in the cardiovascular system, we have analyzed beta3-null mice. Electrophysiological examinations proved the existence of dihydropyridine (DHP)-sensitive. L-type calcium channels in the smooth muscle cells. Beta3-null mice show no apparent changes in smooth muscle contraction and sensitivity to DHP, and normal blood pressure when they are raised on a normal diet, but the 13 subunit deficient mice show elevated blood pressure in response to a high-salt diet, with significant reductions in plasma catecholamine concentrations. Our finding strongly suggests a close relationship between voltage-dependent channels and high blood pressure.

Animals↗

PubMed2005

Stabilizing role of calcium store-dependent plasma membrane calcium channels in action-potential firing and intracellular calcium oscillations.

In many biological systems, cells display spontaneous calcium oscillations (CaOs) and repetitive action-potential firing. These phenomena have been described separately by models for intracellular inositol trisphosphate (IP3)-mediated CaOs and for plasma membrane excitability. In this study, we present an integrated model that combines an excitable membrane with an IP3-mediated intracellular calcium oscillator. The IP3 receptor is described as an endoplasmic reticulum (ER) calcium channel with open and close probabilities that depend on the cytoplasmic concentration of IP3 and Ca2+. We show that simply combining this ER model for intracellular CaOs with a model for membrane excitability of normal rat kidney (NRK) fibroblasts leads to instability of intracellular calcium dynamics. To ensure stable long-term periodic firing of action potentials and CaOs, it is essential to incorporate calcium transporters controlled by feedback of the ER store filling, for example, store-operated calcium channels in the plasma membrane. For low IP3 concentrations, our integrated NRK cell model is at rest at -70 mV. For higher IP3 concentrations, the CaOs become activated and trigger repetitive firing of action potentials. At high IP3 concentrations, the basal intracellular calcium concentration becomes elevated and the cell is depolarized near -20 mV. These predictions are in agreement with the different proliferative states of cultures of NRK fibroblasts. We postulate that the stabilizing role of calcium channels and/or other calcium transporters controlled by feedback from the ER store is essential for any cell in which calcium signaling by intracellular CaOs involves both ER and plasma membrane calcium fluxes.

Action Potentials↗

PubMed2004

L-type calcium channels: the low down.

L-type calcium channels couple membrane depolarization in neurons to numerous processes including gene expression, synaptic efficacy, and cell survival. To establish the contribution of L-type calcium channels to various signaling cascades, investigators have relied on their unique pharmacological sensitivity to dihydropyridines. The traditional view of dihydropyridine-sensitive L-type calcium channels is that they are high-voltage-activating and have slow activation kinetics. These properties limit the involvement of L-type calcium channels to neuronal functions triggered by strong and sustained depolarizations. This review highlights literature, both long-standing and recent, that points to significant functional diversity among L-type calcium channels expressed in neurons and other excitable cells. Past literature contains several reports of low-voltage-activated neuronal L-type calcium channels that parallel the unique properties of recently cloned CaV1.3 L-type channels. The fast kinetics and low activation thresholds of CaV1.3 channels stand in stark contrast to criteria currently used to describe L-type calcium channels. A more accurate view of neuronal L-type calcium channels encompasses a broad range of activation thresholds and recognizes their potential contribution to signaling cascades triggered by subthreshold depolarizations.

Animals↗

PubMed1989

The effects of calcium channel blockade on blood pressure and calcium metabolism.

To study the relation of calcium channel blockade to calcium metabolism, we measured serum ionized calcium (Ca++i0), magnesium (Mg), calcitonin (CT), and 1,25-dihydroxyvitamin D (1,25-D) before and after short-term therapy with verapamil 120 mg three times daily in essential hypertensive subjects on low (10 mEq) and high (200 mEq) dietary sodium intakes. Salt-sensitive compared with salt-insensitive subjects on high v low dietary salt intake had lower Ca++i0 (P less than .05), higher 1,25-D (P less than .02), and a greater hypertensive responsive to verapamil (% delta DBP = 17.7 v -8.2, P less than .05). The % delta DBP was related to the initial CT (r = 0.68, P less than .05), initial 1,25-D (R = -0.89, P less than .01), and to the drug-induced % delta 1,25 D (R = .60, P less than .05). Thus, lower initial calcium and calcitonin levels, higher initial levels of 1,25-D, and a greater drug-induced suppression of 1,25-D were associated with an enhanced hypotensive response to verapamil. Verapamil elevated Ca++i0 (2.46 +/- 0.04 to 2.53 +/- 0.04 2.00 mEq/L, P less than .05), and suppressed Mg (2.00 +/- 0.03 to 1.84 +/- 0.03 mEq/L, P less than .01) and 1,25-D levels (66.7 +/- 8.1 to 51.6 +/- 5.7 pg/mL, P less than .05). These results suggest interactive effects of sodium and calcium metabolism in essential hypertension, especially among salt-sensitive individuals. We conclude that alterations of calcium metabolism may underlie the sensitivity to verapamil therapy and may contribute to its hypotensive effects.

Blood Pressure↗

PubMed1990

Calcium-sensitive inactivation in the gating of single calcium channels.

Voltage-activated calcium channels open and close, or gate, according to molecular transition rates that are regulated by transmembrane voltage and neurotransmitters. Here evidence for the control of gating by calcium was found in electrophysiological records of single, L-type calcium channels in heart cells. Conditional open probability analysis revealed that calcium entry during the opening of a single channel produces alterations in gating transition rates that evolve over the course of hundreds of milliseconds. Such alteration of calcium-channel gating by entry of a favored permeant ion provides a mechanism for the short-term modulation of single-ion channels.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1992

A method for estimation of drug affinity constants to the open conformational state of calcium channels.

The affinity of D600 to calcium channels in the open state has been examined in isolated smooth muscle cells of the rabbit ear artery. Calcium channel currents were measured in high external barium solution by means of the patch-clamp technique. The current inhibition in various D600 concentrations (3-100 microM) on application of trains of short test pulses (20-80 ms) has been studied in nonmodified calcium channels and in cells where the calcium channels were modified by the agonist dihydropyridine (+) 202,791 (100 nM). The kinetics of the peak current decay has been analyzed with a mathematical model which is based on the experimental finding that D600 interacts primarily with calcium channels in the open conformational state. The model approach allows the estimation of drug affinity constants of D600 to the calcium channel in the open conformation. An association rate constant to the open conformational state of D600 of 6.16 x 10(4) M-1 s-1 was estimated. The association rate of the drug was not significantly changed after the calcium channels have been modified with 100 nM (+) 202,791. A method for correction of rate constants for possible drug trapping is discussed.

Animals↗

PubMed2005

Mouse models to study L-type calcium channel function.

Calcium influx through voltage gated L-type Ca2+ channels has evolved as one of the most widely used transmembrane signalling mechanisms in eukaryotic organisms. Although pharmacological inhibitors of L-type Ca2+ channels have an important place in medical therapy, the full therapeutic potential of the 4 L-type Ca2+ channel subtypes has not been explored yet. To dissect the physiological relevance of the L-type Ca2+ channel subtype diversity, gene-targeted mouse models carrying deletions of these channels ("knockout mice") have been generated. This review focuses on recent data from studies in mice lacking the Ca(v)1.2 and Ca(v)1.3 pore subunits, which have elucidated some of the roles of L-type Ca2+ channels as mediators of signalling between cell membrane and intracellular processes like blood pressure regulation, smooth muscle contractility, insulin secretion, cardiac development, and learning and memory.

Animals↗