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At least 649 records · Page 36Linked to original sources

PubMed1987

Reconstitution of the purified receptor for calcium channel blockers.

The purified receptor for calcium channel blockers from rabbit skeletal muscle was reconstituted into phospholipid vesicles. The reconstitution did not alter the stoichiometry of the peptide chains. [3H]PN 200-110 bound to one site with apparent KD and Bmax values of 9.8 nM and 980 pmol/mg protein, respectively. The binding was stereospecific. D-cis-diltiazem and (-) desmethoxyverapamil affected allosterically the binding of dihydropyridines. This demonstrates the coinsertion of specific binding sites for the three calcium channel blocker into phospholipid vesicles.

Allosteric Regulation↗

PubMed1986

Control of PTH secretion is mediated through calcium channels and is blocked by pertussis toxin treatment of parathyroid cells.

Parathyroid hormone secretion is negatively regulated by calcium. We utilized calcium channel agents: +202-791, a calcium channel agonist and -202-791, a calcium channel antagonist, to evaluate the role of calcium channels in PTH secretion. +202-791 inhibited PTH release from bovine parathyroid cells and the antagonist stimulated release. Incubation with pertussis toxin which ADP-ribosylates and inactivates a guanine nucleotide regulatory protein (G-protein) releases the inhibition by the calcium channel agonist. These findings indicate that a G-protein is interposed between the calcium channel and a putative intracellular site controlling PTH secretion.

Animals↗

PubMed2000

Immunohistochemical study on the distribution of the voltage-gated calcium channel alpha(1B) subunit in the mature rat brain.

Many neuronal processes are regulated by calcium influx through voltage-gated calcium channels. Among these calcium channels, the N-type channel has been shown to play a significant role in the regulation of neurotransmitter release. This present report has demonstrated the distribution of the alpha(1B) subunit of the N-type calcium channel in the mature rat brain. The most striking findings were the highest immunoreactivity in the CA1 region of the hippocampus and the clear demarcation in the thalamus. Characteristic patterns of distribution were noted in the cerebral cortex, hippocampus, caudate-putamen, thalamus, and cerebellum. In the cerebral cortex, strong staining was seen in layers II-III and V. In the basal ganglia, the staining intensity was high in the caudate-putamen, whereas there was no immunoreactivity in the globus pallidus. Although the staining intensity was relatively low compared to that of the forebrain, moderate alpha(1B)-IR was found in the dorsal cochlear nucleus and mesencephalic trigeminal nucleus. The detailed features of this study will extend our current knowledge of alpha(1B) subunit distribution in terms of the number of neuroanatomical areas examined, by investigating alpha(1B) subunit protein expression, for the first time.

Animals↗

PubMed2005

Is postoperative calcium channel blocker therapy needed in patients with radial artery grafts?

BACKGROUND: Chronic calcium channel blocker therapy has traditionally been considered necessary in patients carrying a radial artery graft, even in the absence of objective data to support it. This report was conceived to evaluate the angiographic and clinical effects of calcium channel blocker therapy during the first postoperative year. PATIENTS AND RESULTS: A total of 100 consecutive patients who received a radial artery graft at our institution were randomly assigned to receive (n = 53) or not receive (n = 47) calcium channel blocker therapy with oral diltiazem 120 mg/daily started in the early postoperative period. At 1-year follow-up, all patients were reassessed clinically and by Tl 201 myocardial scintigraphy, and 83 of them underwent control angiography. In 12 cases we also evaluated the response of the radial artery to the endovascular infusion of serotonin. No difference in terms of clinical outcome, scintigraphic results, and patency rate was found between patients who received or did not receive calcium channel blocker therapy. Endovascular serotonin infusion evoked an evident spastic reaction of radial artery grafts, not attenuated by calcium channel blocker therapy. CONCLUSION: Calcium channel blocker therapy started immediately after surgery and continued for the first postoperative year does not affect radial artery graft patency and clinical and scintigraphic outcomes. On the basis of these data, the prophylactic use of calcium channel blocker therapy in patients with radial artery grafts seems unsubstantiated.

Aged↗

PubMed1997

Toxic effects of antimalarial drugs in Paramecium: role of calcium channels.

The antimalarial drugs, quinacrine, quinine and mefloquine, as well as the structurally-similar compound, W-7, inhibit calcium-dependent backward swimming and calcium currents in Paramecium calkinsi. These drugs are also toxic to paramecia at high concentrations. Therefore, one site of toxic action of the drugs may be the calcium channel. To test this hypothesis, the toxicity of the antimalarials and W-7 was compared in paramecia with and without calcium channels. Since calcium channels are located on the cilia, calcium channels were removed from the paramecia by deciliating the cells. Deciliated cells were found to be less susceptible to the lethal effects of the antimalarials and W-7 than their ciliated counterparts. Moreover, Pawns, mutants of P. tetraurelia that possess cilia but lack functional calcium channels, were also less susceptible to the antimalarials than wild-type cells. Thus, calcium channels may be one site of toxic action of the antimalarial drugs in paramecia and perhaps in other protists.

Animals↗

PubMed1993

Use of amrinone and glucagon in a case of calcium channel blocker overdose.

Hypotension resulting from calcium channel blocker ingestion often is refractory to standard therapeutic modalities. Amrinone and glucagon have been used separately and in combination with other agents in the treatment of calcium channel blocker overdose. We report the successful use of both amrinone and glucagon in the treatment of a 30-year-old woman who ingested 3.6 g of verapamil and presented with refractory hypotension. The use of the two agents together may provide improved inotropic support with minimal increases in myocardial oxygen consumption. In this case, the combination of amrinone and glucagon was safe and effective in the management of the hemodynamic instability associated with calcium channel blocker overdose.

Adult↗

PubMed2006

The C terminus of the L-type voltage-gated calcium channel Ca(V)1.2 encodes a transcription factor.

Voltage-gated calcium channels play a central role in regulating the electrical and biochemical properties of neurons and muscle cells. One of the ways in which calcium channels regulate long-lasting neuronal properties is by activating signaling pathways that control gene expression, but the mechanisms that link calcium channels to the nucleus are not well understood. We report that a C-terminal fragment of Ca(V)1.2, an L-type voltage-gated calcium channel (LTC), translocates to the nucleus and regulates transcription. We show that this calcium channel associated transcription regulator (CCAT) binds to a nuclear protein, associates with an endogenous promoter, and regulates the expression of a wide variety of endogenous genes important for neuronal signaling and excitability. The nuclear localization of CCAT is regulated both developmentally and by changes in intracellular calcium. These findings provide evidence that voltage-gated calcium channels can directly activate transcription and suggest a mechanism linking voltage-gated channels to the function and differentiation of excitable cells.

Amino Acid Sequence↗

PubMed1987

Characterization of two types of calcium channels in mouse neuroblastoma cells.

1. Two types of voltage-sensitive calcium channels were identified and studied in the neuroblastoma cell line N1E-115. Calcium channel currents as carried by Ba2+ (50 mM) were recorded using the whole-cell variation of the patch-electrode voltage-clamp technique. 2. A transient (type I) inward Ba2+ current was evoked by a step depolarization from a holding potential of -80 mV to potentials more positive than -50 mV. The current amplitude became maximum around -20 mV. 3. A depolarization to potentials more positive than -20 mV evoked a long-lasting (type II) component of the inward Ba2+ current. This component reached its maximum around +10 mV and did not inactivate during a prolonged depolarizing pulse lasting 400 ms. 4. When preceded by a 5 s conditioning pulse to -30 mV, step depolarization failed to evoke a transient current due to inactivation. However, it induced a long-lasting current. 5. A transient current isolated as the component sensitive to conditioning depolarization became faster in its time course and smaller in its amplitude with membrane depolarization. The current direction was still inward at +60 mV. 6. From the differential voltage sensitivity and the independent channel activity described above, calcium channels responsible for the transient current (type I channel) and those responsible for the long-lasting current (type II channel) were considered to be two different entities. 7. Cd2+ preferentially blocked type II channels, whereas La3+ was a highly potent blocker for both types of calcium channels. 8. The relative potency for block by polyvalent cations was as follows (apparent dissociation constant in microM): La3+, 1.5 much greater than Ni2+, 47 greater than Cd2+, 160 = Co2+, 160 for type I channels, and La3+, 0.9 greater than Cd2+, 7.0 much greater than Ni2+, 280 greater than Co2+, 560 for type II channels. 9. The two types of calcium channels were equally sensitive to the temperature. The current amplitude was reduced by cooling below 30 degrees C. The temperature coefficient (Q10) value was estimated to be 3.0 between 20 and 30 degrees C, and 15.0 below 20 degrees C. Above 30 degrees C, warming reduced the amplitude slightly. 10. External application of dibutyryl adenosine 3',5'-phosphate (dibutyryl cyclic AMP) (1 mM) caused an increase in the amplitude of the type II current by 30-50%, while failing to enhance the type I component.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1998

No association between calcium channel blocker use and confirmed bleeding peptic ulcer disease.

Calcium channel antagonists are commonly used drugs that have recently been reported to be associated with an increased incidence of gastrointestinal hemorrhage. We performed a retrospective cohort study among 105,824 enrollees of the Tennessee Medicaid program 65 years of age or older between 1984 and 1986. Exposure to calcium channel blockers and other medications was determined from pharmacy files. Hospitalization for bleeding peptic ulcers was identified by hospital claims and verified by a review of the medical record. Univariate estimates of relative risk for current users of calcium channel blockers and beta-blocker users were 1.8 (95% confidence interval (CI) 1.2-2.7) and 1.1 (95% CI 0.7-1.6) (reference group was nonuse of either). After adjustment for potential confounders, the relative risks for bleeding peptic ulcer among current users of calcium channel blockers and beta blockers were 1.1 (95% CI 0.7-1.7) and 1.0 (95% CI 0.7-1.6), respectively, when compared with those who used neither drug. In this population, after controlling for important confounders, there was no increased risk for hospitalization with bleeding peptic ulcer among users of calcium channel blockers.

Adrenergic beta-Antagonists↗

PubMed1998

Modulation of human neuronal alpha 1E-type calcium channel by alpha 2 delta-subunit.

Calcium channels are composed of a pore-forming subunit, alpha 1, and at least two auxiliary subunits, beta- and alpha 2 delta-subunits. It is well known that beta-subunits regulate most of the properties of the channel. The function of alpha 2 delta-subunit is less understood. In this study, the effects of the calcium channel alpha 2 delta-subunit on the neuronal alpha 1E voltage-gated calcium channel expressed in Xenopus oocytes was investigated without and with simultaneous coexpression of either the beta 1b- or the beta 2a-subunit. Most aspects of alpha 1E function were affected by alpha 2 delta. Thus alpha 2 delta caused a shift in the current-voltage and conductance-voltage curves toward more positive potentials and accelerated activation, deactivation, and the installation of the inactivation process. In addition, the efficiency with which charge movement is coupled to pore opening assessed by determining ratios of limiting conductance to limiting charge movement was decreased by alpha 2 delta by factors that ranged from 1.6 (P < 0.01) for alpha 1E-channels to 3.0 (P < 0.005) for alpha 1E beta 1b-channels. These results indicate that alpha 2 delta facilitates the expression and the maturation of alpha 1E-channels and converts these channels into molecules responding more rapidly to voltage.

Animals↗

PubMed1999

L-type voltage-gated calcium channels modulate kainic acid neurotoxicity in cerebellar granule cells.

This study reports on the regulation of kainate neurotoxicity in cerebellar granule cells by calcium entry through voltage-gated calcium channels and by calcium release from internal cellular stores. Kainate neurotoxicity was prevented by the AMPA selective antagonist LY 303070 (10 microM). Kainate neurotoxicity was potentiated by cadmium, a general voltage-gated calcium channel blocker, and the L-type voltage-gated calcium channel blocker nifedipine. The antagonists of intracellular Ca2+ ([Ca2+]i) release, thapsigargin and ryanodine, were also able to potentiate kainate neurotoxicity. Kainate treatment elevated [Ca2+]i concentration with a rapid initial increase that peaked at 1543 nM and then declined to plateau at approximately 400 nM. Nifedipine lowered the peak response to 764 nM and the plateau response to approximately 90 nM. Thapsigargin also lowered the kainate-induced increase in [Ca2+]i (640 nM peak, 125 nM plateau). The ryanodine receptor agonist caffeine eliminated the kainate-induced increase in [Ca2+]i, and reduced kainate neurotoxicity. Kainate neurotoxicity potentiated by nifedipine was not prevented by RNA or protein synthesis inhibitors, nor by the caspase inhibitors YVAD-CHO and DEVD-CHO. Neither DNA laddering nor the number of apoptotic nuclei were increased following treatment with kainate and nifedipine. Increased nuclear staining with the membrane impermeable dye propidium iodide was observed immediately following kainate treatment, indicating a loss of plasma membrane integrity. Thus, kainate neurotoxicity is prevented by calcium entry through L-type calcium channels.

1-Methyl-3-isobutylxanthine↗

PubMed1989

Nicardipine, a new calcium channel blocker: role for vascular selectivity.

Calcium channel blockers are important drugs for the treatment of chronic stable angina. However, negative inotropic and dromotropic effects may limit their usefulness in patients with atrioventricular conduction abnormalities or left ventricular dysfunction. A new generation of calcium channel blockers will soon be available that have a more vascular selective action than currently available agents. Of the new agents, nicardipine has been most extensively studied. In experimental studies, nicardipine is more specific for vascular smooth muscle than for cardiac smooth muscle and for coronary than peripheral vasculature. In controlled trials, nicardipine exhibited efficacy and safety that was comparable to older calcium blockers or beta blockers. However, nicardipine was associated with minimal negative inotropic or dromotropic effects even in patients with existing left ventricular dysfunction. Thus, nicardipine may have an advantage over existing calcium channel blockers, especially in patients with underlying cardiac disease.

Angina Pectoris↗

PubMed1991

Reversible uncoupling of inactivation in N-type calcium channels.

N-type calcium channels are thought to be expressed specifically in neuronal cells and to have a dominant role in the control of neurotransmitter release from sympathetic neurons. But their unitary properties are poorly understood and the separation of neuronal Ca2+ current into components carried by N-type or L-type Ca2+ channels is controversial. Here we show that individual N-type Ca2+ channels in sympathetic neurons can carry two kinetically distinct components of current, one that is rapidly transient and one that is long lasting. The mechanism that gives rise to these two components is unexpected for Ca2+ channels: a test depolarization elicits either a rapidly inactivating, single short burst with an average duration of 40 ms, or sustained, noninactivating channel activity lasting for over 1 s. The switching between inactivating and noninactivating activity is a slow process, the occurrence of each type of unitary kinetic behaviour remaining statistically correlated over several seconds. Variable coupling of inactivation in N-type Ca2+ channels could be an effective mechanism for the modulation of neuronal excitability and synaptic plasticity.

Animals↗

PubMed2000

Roles of high-voltage-activated calcium channel subtypes in a vertebrate spinal locomotor network.

Lamprey spinal cord neurons possess N-, L-, and P/Q-type high-voltage-activated (HVA) calcium channels. We have analyzed the role of the different HVA calcium channels subtypes in the overall functioning of the spinal locomotor network by monitoring the influence of their specific agonists and antagonists on synaptic transmission and on N-methyl-D-aspartate (NMDA)-elicited fictive locomotion. The N-type calcium channel blocker omega-conotoxin GVIA (omega-CgTx) depressed synaptic transmission from excitatory and inhibitory interneurons. Blocking L-type and P/Q-type calcium channels with nimodipine and omega-agatoxin, respectively, did not affect synaptic transmission. Application of omega-CgTx initially decreased the frequency of the locomotor rhythm, increased the burst duration, and subsequently increased the coefficient of variation and disrupted the motor pattern. These effects were accompanied by a depression of the synaptic drive between neurons in the locomotor network. Blockade of L-type channels by nimodipine also decreased the frequency and increased the duration of the locomotor bursts. Conversely, potentiation of L-type channels increased the frequency of the locomotor activity and decreased the duration of the ventral root bursts. In contrast to blockade of N-type channels, blockade or potentiation of L-type calcium channels had no effect on the stability of the locomotor pattern. The P/Q-type calcium channel blocker omega-agatoxin IVA had little effect on the locomotor frequency or burst duration. The results indicate that rhythm generation in the spinal locomotor network of the lamprey relies on calcium influx through L-type and N-type calcium channels.

Animals↗

PubMed1995

Antisense depletion of beta-subunits modulates the biophysical and pharmacological properties of neuronal calcium channels.

1. The role of the voltage-dependent calcium channel (VDCC) beta-subunit has been examined in cultured rat dorsal root ganglion neurones (DRGs). An antipeptide antibody was raised and this recognized proteins corresponding to beta-subunits in a number of preparations. Immunoreactivity for the VDCC beta-subunit in DRGs was concentrated on the internal side of the plasma membrane but was also present in the cytoplasm. 2. A twenty-six-mer antisense oligonucleotide with homology to all published VDCC beta-subunit sequences was microinjected into individual cells, and maximal depletion of VDCC beta-subunit immunoreactivity was observed after 108 h suggesting a half-life for the turnover of the beta-subunit greater than 50 h. No depletion was obtained with nonsense oligonucleotide. 3. The effect of depletion of VDCC beta-subunit immunoreactivity on calcium channel currents in these cells was a reduction in amplitude of the maximum current of about 47%, and a shift in the voltage dependence of current activation of about +7 mV. These effects are the converse of those observed following co-expression of cloned beta- with alpha 1-subunits in oocytes and other expression systems. 4. The ability of the 1,4-dihydropyridine (DHP) agonist Bay K 8644 to enhance calcium channel currents was greatly reduced following depletion of beta-subunit immunoreactivity. This result is in agreement with the finding in several systems that co-expression of the beta-subunit with alpha 1-subunits results in an increased number of DHP binding sites. 5. These results show that calcium channel beta-subunits form part of native neuronal calcium channels and modify their biophysical and pharmacological properties.

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

PubMed2006

The Src homology 3 domain of the beta-subunit of voltage-gated calcium channels promotes endocytosis via dynamin interaction.

High voltage-gated calcium channels enable calcium entry into cells in response to membrane depolarization. Association of the auxiliary beta-subunit to the alpha-interaction-domain in the pore-forming alpha1-subunit is required to form functional channels. The beta-subunit belongs to the membrane-associated guanylate kinase class of scaffolding proteins containing a Src homology 3 and a guanylate kinase domain. Although the latter is responsible for the high affinity binding to the alpha-interaction domain, the functional significance of the Src homology 3 domain remains elusive. Here, we show that injection of isolated beta-subunit Src homology 3 domain into Xenopus laevis oocytes expressing the alpha1-subunit reduces the number of channels in the plasma membrane. This effect is reverted by coexpressing alpha1 with a dominant-negative mutant of dynamin, a GTPase involved in receptor-mediated endocytosis. Full-length beta-subunit also down-regulates voltage-gated calcium channels but only when lacking the alpha-interaction domain. Moreover, isolated Src homology 3 domain and the full-length beta-subunit were found to interact in vitro with dynamin and to internalize the distantly related Shaker potassium channel. These results demonstrate that the beta-subunit regulates the turnover of voltage-gated calcium channels and other proteins in the cell membrane. This effect is mediated by dynamin and depends on the association state of the beta-subunit to the alpha1-pore-forming subunit. Our findings define a novel function for the beta-subunit through its Src homology 3 domain and establish a link between voltage-gated calcium channel activity and the cell endocytic machinery.

Animals↗

PubMed1985

Calcium-channel blockers and systemic hypertension.

Calcium-channel blockers selectively inhibit transmembrane flux of calcium in excitable tissues. Their ability to block calcium-mediated electromechanical coupling in contractile tissue produces peripheral vasodilation and has led to interest in their use for systemic hypertension. A postulated involvement of calcium in the development of the increased vascular tone of hypertension makes these agents appear particularly attractive for use as vasodilators. Clinical trials suggest a potentially important role for the calcium-channel blockers in the treatment of systemic hypertension.

Acute Disease↗

PubMed1994

Calcium anti-ionophoretic effect of some calcium channel blockers in rat liver mitochondria.

Beyond their classical action on calcium channels, some calcium channel blockers also exhibit a calcium anti-ionophoretic effect. We studied this effect on respiratory control and Ca2+ fluxes in a mitochondrial model to compare calcium antagonists chosen among three clinical classes: vascular, cardiac, and mixed effects. Synthetic calcium ionophore A23187 decreases respiratory control and modifies Ca2+ fluxes. We show that calcium antagonists partially restore the parameters altered by A23187. By calculating the percentage of restoration, we found that vascular drugs exhibit a strong anti-ionophoretic effect, cardiac drugs exert no significant effect, and mixed calcium antagonists exert an intermediate effect. Thus, it appears possible to link the intensity of calcium anti-ionophoretic effect with the clinical interest of a calcium antagonist.

Animals↗