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At least 235 records · Page 13Linked to original sources
PubMed1987

Identification of an alpha subunit of dihydropyridine-sensitive brain calcium channels.

Voltage-sensitive calcium channels in different tissues have diverse functional properties. Polyclonal antibodies (PAC-2) against the alpha subunits of purified rabbit skeletal muscle calcium channels immunoprecipitated calcium channels labeled with the dihydropyridine PN200-110 from both skeletal muscle and brain. The immunoreactivity of PAC-2 with the skeletal muscle channel was greater than that with the brain calcium channel and was absorbed only partially by prior treatment with the brain channel. PAC-2 specifically recognized a large peptide in synaptic plasma membranes of rabbit brain with an apparent molecular size of 169,000 daltons. This protein resembles an alpha subunit of the skeletal muscle calcium channel in apparent molecular weight, antigenic properties, and electrophoretic behavior after reduction of disulfide bonds. Thus, the dihydropyridine-sensitive calcium channel of rabbit brain has an alpha subunit that is homologous, but not identical, to those of the skeletal muscle calcium channel. The different functional properties of these two calcium channels may result from minor variations in structurally similar components.

Animals↗
PubMed1992

Platelet-derived growth factor activation of gastric mucosal calcium channels.

Gastric mucosal calcium channel complex was isolated from the solubilized epithelial cell membranes by affinity chromatography on wheat germ agglutinin. The complex following labeling with [3H]PN200-100 was reconstituted into phospholipid vesicles which exhibited active 45Ca2+ uptake. The channels responded in a dose dependent manner to dihydropyridine calcium antagonist, PN200-110, which at 0.5 microM exerted maximal inhibitory affect of 66% on 45Ca2+ uptake, while a 52% enhancement in 45Ca2+ uptake occurred with a specific calcium channel activator, BAY K8644. On platelet-derived growth factor (PDGF) binding in the presence of ATP, channels showed an increase in protein tyrosine phosphorylation of 55 and 170kDa subunits of calcium channel. Such phosphorylated channels following reconstitution into vesicles displayed a 78% greater 45Ca2+ uptake. The results point towards the importance of PDGF in the regulation of gastric mucosal calcium homeostasis.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

Comparison of lowest energy conformations of dimethylcurine and methoxyverapamil: evidence of ternary association of calcium channel, Ca2+, and calcium entry blockers.

Verapamil and dimethylcurine are Ca2+ entry blockers of essentially different chemical structures which presumably bind to the same arylalkylamine receptor of the L-type Ca channel. A systematic conformational analysis of methoxyverapamil (D-600) and dimethylcurine has been carried out using a molecular mechanics method. The lowest minimum-energy conformations of D-600 are predisposed to chelate Ca2+ by four oxygen atoms of the stacked methoxyphenyl moieties. Comparison of the lowest energy conformations of D-600-Ca2+ and dimethylcurine revealed a similar spatial disposition of cationic groups and methoxyphenyl moieties in the two compounds. A three-dimensional model of arylalkylamine receptor was suggested which incorporates two nucleophilic areas of the Ca channel. Dimethylcurine binds to these areas by its quaternary amine functions, whereas D-600 does so by amine function and via coordinated Ca2+. The results support the hypotheses on ternary complex formation between the ligands of Ca channel, their receptors, and Ca2+.

Calcium↗
PubMed2003

Regulation of presynaptic calcium channels by synaptic proteins.

Calcium entry into nerve termini via voltage gated calcium channels is an essential step in neurotransmission. Consequently, second messenger regulation of calcium channel activity modulates synaptic activity. It has been suggested that calcium channels must physically couple to the release machinery, and a physical interaction between a synaptic protein interaction (synprint) site contained within mammalian presynaptic calcium channels and synaptic proteins such as syntaxin 1, SNAP-25, and synaptotagmin has been demonstrated. Interestingly, synaptic calcium channels in invertebrates lack this region. In invertebrates, synaptic transmission is instead dependent on a presynaptic calcium channel splice variant that can physically associate with the adaptor proteins Mint-1 and CASK. We suggest that in the absence of a synprint region, these proteins may localize calcium channels to the synaptic release machinery. The interactions between synaptic proteins and mammalian N-type calcium channels serves to regulate calcium channel activity directly, as well as indirectly by altering second messenger regulation of the channels. This provides for a feedback mechanism that allows the fine-tuning of calcium channel activity during various steps in neurotransmitter release. This does not occur with invertebrate synaptic calcium channel homologs, suggesting that the regulation of calcium channel activity by synaptic proteins is a mechanism unique to vertebrates.

Animals↗
PubMed1995

Effects of calcium channel antagonists on calcium entry and glutamate release from cultured rat cerebellar granule cells.

Using a range of Ca2+ channel blockers we have investigated the Ca2+ channel subtypes that mediate the depolarisation-induced elevation of the intracellular free Ca2+ concentration ([Ca2+]i) and glutamate release from cultured rat cerebellar granule cells. omega-Conotoxin-GVIA had little effect on either the transient or plateau phase of the depolarisation-induced [Ca2+]i rise or on glutamate release, ruling out a significant role for N-type Ca2+ channels. Nifedipine substantially inhibited the initial transient rise in [Ca2+]i and the plateau phase of the [Ca2+]i rise and glutamate release, suggesting the involvement of L-type Ca2+ channels. Both omega-agatoxin and omega-conotoxin-MVIIC also inhibited the transient rise in [Ca2+]i and glutamate release but not the plateau phase of the [Ca2+]i rise. The inhibitions by nifedipine were not increased by coaddition of omega-conotoxin-MVIIC, suggesting overlapping sensitivity to these channel blockers. These data show that glutamate release from granule cells in response to depolarisation with a high KCI level involves Ca2+ currents that are sensitive to nifedipine, omega-agatoxin-IVA, and also omega-conotoxin-MVIIC. The overlapping sensitivity of the channels to these toxins prevents attribution of any of the phases of the [Ca2+]i rise or glutamate release to distinct P-, Q-, or O-type Ca2+ currents.

Animals↗
PubMed1984

Molecular pharmacology of the calcium channel: evidence for subtypes, multiple drug-receptor sites, channel subunits, and the development of a radioiodinated 1,4-dihydropyridine calcium channel label, [125I]iodipine.

Radiolabeled Ca2+ antagonists (1,4-dihydropyridines, verapamil, and D-cis-diltiazem) were used to study voltage-operated Ca2+ channels in different excitable tissues. The concept of three subtypes of Ca2+ channels, represented by brain, heart, and skeletal-muscle isoreceptors for 1,4-dihydropyridines, is developed. The three subtypes are characterized by a variety of criteria. Despite the biochemical differences between the subtypes, they have the same Mr in situ by target-size analysis (Mr approximately equal to 180,000, when evaluated by [3H]nimodipine). The concept of the metalloprotein nature of the channel and the interaction of channel drugs with the Me2+ binding sites of the ionic pore is demonstrated. Distinct but interacting drug-receptor sites of the Ca2+ channel are found by direct labeling as well as indirectly by drug competition studies. We distinguish between the 1,4-dihydropyridine site, the verapamil site, and the D-cis-diltiazem site. Each receptor site can exist in high and low-affinity state; the distribution of receptor sites in these states is regulated by temperature, ions, and drugs. The concept of intrinsic activity of drugs to stabilize the high-affinity state is exemplified for the 1,4-dihydropyridines. A change in the channel architecture is induced by binding of D-cis-diltiazem to its drug receptor site. This is proven by target-size analysis of the channel in situ. Partially purified t-tubule membranes from skeletal muscle are an extremely rich source of Ca2+ channel drug-receptor sites. The stoichiometry was determined in this preparation and found to be four verapamil:two 1,4-dihydropyridine:one D-cis-diltiazem site. A novel Ca2+ channel probe, [125I]iodipine (2,200 Ci/mmol), was synthetized, and the properties of this ligand are presented.

Animals↗
PubMed1986

Direct effects of calcium channel blockers on duodenal calcium transport in vivo.

The direct effects of verapamil, diltiazem and nifedipine on duodenal calcium transport were assessed in rats by the in vivo ligated loop technique, using luminal calcium concentrations at which active and passive transport mechanisms predominate (2 and 50 mM Ca, respectively). At 2 mM Ca, addition of verapamil (0.3-10 mM) to the luminal solution caused a concentration-dependent decrease in calcium lumen-to-plasma uptake and an increase in calcium plasma-to-lumen translocation, such that at 10 mM verapamil there was a net secretion of calcium into the duodenal lumen. In contrast, nifedipine (0.3-3 mM) was without effect on calcium transport, and diltiazem reduced calcium lumen-to-plasma uptake and net calcium absorption only at 10 mM, without influencing plasma-to-lumen translocation. The verapamil-induced increase in calcium plasma-to-lumen translocation was abolished by bile duct ligation. Calcium transport was unaffected by any calcium channel blocker at 50 mM luminal calcium. Thus, verapamil can directly influence active calcium translocation in the intestine, in vivo, and may affect calcium homeostasis during chronic oral treatment with this drug.

Animals↗
PubMed1991

Pharmacokinetic interactions with calcium channel antagonists (Part I).

Calcium channel antagonists are a diverse class of drugs widely used in combination with other therapeutic agents. The potential exists for many clinically significant pharmacokinetic interactions between these and other concurrently administered drugs. The mechanisms of calcium channel antagonist-induced changes in drug metabolism include altered hepatic blood flow and impaired hepatic enzyme metabolising activity. Increases in serum concentrations and/or reductions in clearance have been reported for several drugs used with a number of calcium channel antagonists. A number of reports and studies of calcium channel antagonist interactions have yielded contradictory results and the clinical significance of pharmacokinetic changes seen with these agents is ill-defined. The first part of this article deals with interactions between calcium antagonists and marker compounds, theophylline, midazolam, lithium, doxorubicin, oral hypoglycaemics and cardiac drugs.

Anti-Arrhythmia Agents↗
PubMed2006

Role of calcium influx through voltage-operated calcium channels and of calcium mobilization in the physiology of Schistosoma mansoni muscle contractions.

We tested the hypothesis that voltage-operated Ca2+ channels mediate an extracellular Ca2+ influx in muscle fibres from the human parasite Schistosoma mansoni and, along with Ca2+ mobilization from the sarcoplasmic reticulum, contribute to muscle contraction. Indeed, whole-cell voltage clamp revealed voltage-gated inward currents carried by divalent ions with a peak current elicited by steps to +20 mV (from a holding potential of -70 mV). Depolarization of the fibres by elevated extracellular K+ elicited contractions that were completely dependent on extracellular Ca2+ and inhibited by nicardipine (half inhibition at 4.1 microM). However these contractions were not very sensitive to other classical blockers of voltage-gated Ca2+ channels, indicating that the schistosome muscle channels have an atypical pharmacology when compared to their mammalian counterparts. Futhermore, the contraction induced by 5 mM caffeine was inhibited after depletion of the sarcoplasmic reticulum either with thapsigargin (10 microM) or ryanodine (10 microM). These data suggest that voltage-operated Ca2+ channels do contribute to S. mansoni contraction as does the mobilization of stored Ca2+, despite the small volume of sarcoplasmic reticulum in schistosome smooth muscles.

Animals↗
PubMed1996

Adenosine inhibits L- and N-type calcium channels in pituitary melanotrophs. Evidence for the involvement of a G protein in calcium channel gating.

It has been previously demonstrated that activation of A1 adenosine receptors in frog melanotrophs causes inhibition of spontaneous action potential discharges and alpha-melanocyte-stimulating hormone secretion. In the present study, we have investigated the effect of adenosine on high-voltage-activated (HVA) calcium currents in cultured melanotrophs, using the whole-cell variant of the patch-clamp technique with barium as a charge carrier. Adenosine and the specific A1 adenosine receptor agonist R-PIA (50 microM each) produced a decrease of the amplitude of the barium current, while the selective A2 adenosine receptor agonist CGS 21680 did not affect the current. The inhibitory effect of R-PIA was observed throughout the activation range of the current, with stronger responses at more positive potentials. R-PIA inhibited both the L- and N-type components of the current, the effect on the N-component being two-fold higher than on the L-component. The inhibitory effect of R-PIA was rendered irreversible by addition of GTP gamma S (100 microM) to the intracellular solution. Pre-treatment of the cells with pertussis toxin (1 microgram/ml; 12 h) totally abolished the effect of R-PIA on the HVA calcium channels. Conversely, addition of a high concentration of cAMP (100 microM) together with the phosphodiesterase inhibitor IBMX (100 microM) to the intracellular solution did not modify the effect of R-PIA on the current. It is concluded that, in frog melanotrophs, adenosine induces inhibition of L- and N-calcium currents and that this effect is mediated by a pertussis toxin-sensitive G protein. Our data also indicate that the inhibitory effect of adenosine on the calcium currents is not mediated by inhibition of adenylyl cyclase.

1-Methyl-3-isobutylxanthine↗
PubMed1998

Acute antihypertensive effects of calcium channel blockers are not affected by calcium supplementation in patients with essential hypertension.

The study was designed to investigate whether the acute antihypertensive effects of calcium channel blockers are affected by calcium supplementation in patients with essential hypertension. The antihypertensive effects of calcium channel blockers (oral manidipine or intravenous nicardipine) were studied before and during calcium supplementation (1200 mg/day for 8 weeks) in 30 hospitalized patients with essential hypertension. The averages of systolic and diastolic blood pressure during a 24-hour period were not decreased by calcium supplementation. The acute antihypertensive effects of the calcium channel blockers nicardipine (0.25, 0.5, 1.5, 2.0 micrograms/kg/min, intravenous infusion) or manidipine (20 mg, once a day, orally) were not enhanced by calcium supplementation. Thus, calcium channel blockers can be safely combined with calcium supplementation in terms of blood pressure.

Administration, Oral↗
PubMed1987

Photoaffinity labelling of the cardiac calcium channel. (-)-[3H]azidopine labels a 165 kDa polypeptide, and evidence against a [3H]-1,4-dihydropyridine-isothiocyanate being a calcium-channel-specific affinity ligand.

The arylazide 1,4-dihydropyridine (-)-[3H]azidopine binds to a saturable population of sites in guinea-pig heart membranes with a dissociation constant (KD) of 30 +/- 7 pM and a density (Bmax.) of 670 +/- 97 fmol/mg of protein. This high-affinity binding site is assumed to reside on voltage-operated calcium channels because reversible binding is blocked stereoselectively by 1,4-dihydropyridine channel blockers and by the enantiomers of Bay K 8644. A low-affinity (KD 25 +/- 7 nM) high-capacity (Bmax. 21.6 +/- 9 pmol/mg of protein) site does not bind (-)- or (+)-Bay K 8644, but is blocked by high concentrations (greater than 500 nM) of dihydro-2,6-dimethyl-4-(2-isothiocyanatophenyl)-3,5-pyridinedicarboxy lic acid dimethyl ester (1,4-DHP-isothiocyanate) or, e.g., (+/-)-nicardipine. (-)-[3H]Azidopine was photoincorporated covalently into bands of 165 +/- 8, 39 +/- 2 and 35 +/- 3 kDa, as determined by SDS/polyacrylamide-gel electrophoresis. Labelling of the 165 kDa band is protected stereoselectively by 1,4-dihydropyridine enantiomers at low (nM) concentrations and by (-)- and (+)-Bay K 8644, whereas the lower-Mr bands are not. Thus, only the 165 kDa band is the calcium-channel-linked 1,4-dihydropyridine receptor. Photolabelling of the 39 or 35 kDa bands was only blocked by 10 microM-1,4-DHP-isothiocyanate or 50 microM-(+/-)-nicardipine but not by 10 microM-(-)-Bay K 8644. [3H]-1,4-DHP-isothiocyanate binds to guinea-pig heart membranes with a KD of 0.35 nM and dissociates with a k-1 of 0.2 min-1 at 30 degrees C. [3H]-1,4 DHP-isothiocyanate irreversibly labels bands of 39 and 35 kDa which are protected by greater than 10 microM-(+/-)-nicardipine or unlabelled ligand but not by 10 microM-(-)-Bay K 8644. Thus, [3H]-1,4-DHP-isothiocyanate is not an affinity probe for the calcium channel.

Affinity Labels↗
PubMed1998

Study on the possible involvement of protein kinases in the modulation of brain presynaptic sodium channels; comparison with calcium channels.

A possible modulatory role of kinases on voltage sensitive Na+ channels of presynaptic brain nerve endings was investigated by testing the effect of several kinase activators and inhibitors on the elevation of [Nai] induced by veratridine in mouse brain synaptosomes loaded with a selective Na+ indicator dye. Veratridine (20 microM) increases the basal [Nai] level (20 mM) more than twofold. This increase is independent of external Ca2+, but abolished by tetrodotoxin (1 microM). Activation of cAMP dependent protein kinase with forskolin or cAMP analogs, or of protein kinase C with diacylglycerol did not affect the veratridine-induced elevation in [Nai]. Drugs reported to inhibit calmodulin-dependent events, as well as the regulatory domain of protein kinase C, were potent and effective inhibitors of the increase in [Nai] induced by veratridine, as well as other veratridine induced responses, namely elevation of [Cai] (monitored with the Ca2+ indicator dye fura-2) and neurotransmitter (GABA) release. Drugs that inhibit kinases by binding to the catalytic site were ineffective, however, as was the phosphatase inhibitor, okadaic acid. A selective inhibitor of Ca2+ and calmodulin dependent protein kinase II also did not affect the elevation of [Nai] induced by veratridine, but markedly diminished the elevation of [Cai] induced by depolarization either with veratridine or with high K+ (15 and 30 mM). On the basis of these results it is concluded that, the dramatic inhibition exerted by some of the drugs tested on the elevation of [Nai] induced by veratridine is not due to their effects on kinases, but to a possible interaction of these compounds with an intracellular site of the Na+ channel. On the other hand, while Ca2+ and calmodulin dependent protein kinase II is unable to modulate brain presynaptic voltage sensitive Na+ channels, it facilitates the activation of brain presynaptic voltage sensitive Ca2+ channels.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2005

Sensing of lysophospholipids by TRPC5 calcium channel.

TRPC calcium channels are emerging as a ubiquitous feature of vertebrate cells, but understanding of them is hampered by limited knowledge of the mechanisms of activation and identity of endogenous regulators. We have revealed that one of the TRPC channels, TRPC5, is strongly activated by common endogenous lysophospholipids including lysophosphatidylcholine (LPC) but, by contrast, not arachidonic acid. Although TRPC5 was stimulated by agonists at G-protein-coupled receptors, TRPC5 activation by LPC occurred downstream and independently of G-protein signaling. The effect was not due to the generation of reactive oxygen species or because of a detergent effect of LPC. LPC activated TRPC5 when applied to excised membrane patches and thus has a relatively direct action on the channel structure, either because of a phospholipid binding site on the channel or because of sensitivity of the channel to perturbation of the bilayer by certain lipids. Activation showed dependence on side-chain length and the chemical head-group. The data revealed a previously unrecognized lysophospholipid-sensing capability of TRPC5 that confers the property of a lipid ionotropic receptor.

Animals↗
PubMed1992

Effects of antiepileptic drugs, calcium channel blockers and other compounds on seizures induced by activation of voltage-dependent L calcium channel in DBA/2 mice.

1. The convulsant activity of the calcium voltage L-channel agonist Bay k 8644 was studied in genetically epilepsy prone DBA/2 mice. 2. Seizures were induced by intracerebroventricular injection of Bay k 8644. 3. These seizures were reversed by some calcium channel blockers such as dihydropyridines, some excitatory amino acid antagonists such as 2-amino-7-phosphonoeptanoate and CPPene, 2-chloro-adenosine, some anticonvulsant drugs such as magnesium valproate, diazepam and clonazepam and two kappa opioid agonists (U-50488H and U-54494A). 4. The remaining antiepileptic drugs (carbamazepine, phenytoin, phenobarbital and trimethadione) were ineffective in this respect. Other anticonvulsant compounds such as dizocilpine (MK 801), ketamine and drugs enhancing GABAergic transmission did not significantly affect the clonic phase of the seizures induced by Bay k 8644. 5. These results show that Bay k 8644 seizures are relatively resistant to some anticonvulsant compounds. The role of some neurotransmitters on seizures induced by Bay k 8644 is discussed.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2001

The risk of limb deficiencies and other congenital abnormalities in children exposed in utero to calcium channel blockers.

AIM: Calcium channel blockers given to pregnant rats have shown an increased prevalence of digital and limb defects and their safety in pregnant women has thus been questioned. We examined the risk of malformations following exposure in utero to calcium channel blockers. METHOD: We conducted a nationwide case-control study based on the Hungarian Case-Control Surveillance of Congenital Abnormalities and identified 22,865 cases with congenital abnormalities and 31,151 population controls during the period 1980-1996. Data on drug exposure were obtained from official questionnaires and obligatory prenatal care logbooks. RESULTS: Among the cases, 586 mothers (2.6%) had been exposed to calcium channel blockers during pregnancy compared with 907 controls (2.4%). The overall prevalence ratios for 17 congenital abnormalities varied between 1.1 and 1.4, and there was no significant increased risk of limb deficiencies or other congenital abnormalities. CONCLUSION: Our data did not indicate an increased prevalence of congenital abnormalities in offspring exposed to calcium channel blockers in utero.

Abnormalities, Drug-Induced↗
PubMed2000

Permanently charged chiral 1,4-dihydropyridines: molecular probes of L-type calcium channels. Synthesis and pharmacological characterization of methyl(omega-trimethylalkylammonium) 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate iodide, calcium channel antagonists.

We report the synthesis of the single enantiomers of permanently charged dihydropyridine derivatives (DHPs with alkyl linker lengths of two and eight carbon atoms) and their activities on cardiac and neuronal L-type calcium channels. Permanently charged chiral 1,4-dihydropyridines and methyl (omega)-trimethylalkylammonium) 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate iodides were synthesized in high optical purities from (R)-(-) and (S)-(+)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-3-+ ++pyridinecarboxylic acid, obtained by resolution of racemic 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-3-pyridi necarboxylic acid. Competition binding experiments with radioligand [3H]-(+)-PN200-110 and the block of whole cell barium currents through L-type calcium channels in GH4C1 cells show that the compounds with the eight-carbon alkyl linker optimally block the L-type Ca2+ channels, and that the S-enantiomer is more potent than the R-enantiomer.

Animals↗