Kinetic modulation of guinea‐pig cardiac L‐type calcium channels by fendiline and reversal of the effects of Bay K 8644

Schultze-Seemann, Wolfgang; Tripathi, O.; Tritthart, H. A.

doi:10.1111/j.1476-5381.1992.tb14308.x

Cited by 14 publications

(4 citation statements)

References 23 publications

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“…Suppression of Ca channel currents in cardiac tissue have been reported with higher concentrations of BayK (1-5 M) and with stimulation paradigms that either hold the cells at more positive membrane potentials (e.g., ϾϪ50 mV) or pulse to positive potentials more frequently (0.1 Hz) than the paradigms employed in this work. Inhibition of L-type Ca channel current by BayK in the presence of the diphenylalkalamine, fendiline, has also been described in guinea pig cardiac myocytes and was attributed to changes in affinity of the DHP-receptor site for BayK (Schreibmayer et al, 1992). This effect of BayK could not be repeated in the presence of verapamil, diltiazem, or nifedipine, nor was it observed when BayK alone was added.…”

Section: Ca Channel Pharmacologymentioning

confidence: 80%

High‐voltage‐activated calcium channels in Müller cells acutely isolated from tiger salamander retina

Welch

Wood

Jollimore

et al. 2004

Glia

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Muller cells mediate retinal function by stabilizing the ionic environment and signal glial network activity via calcium waves. Using whole-cell patch clamp recording, we describe a high-voltage-activated, slowly inactivating Ca channel current in isolated salamander Muller cells that has unusual pharmacological properties. The Ca channel current has an activation midpoint of approximately -8 mV and an inactivation midpoint of approximately -26 mV in 10 mM Ba2+. The time constant for inactivation is approximately 380 ms at potentials positive to zero. The current is blocked by Cd2+ with an EC50 of <100 nM. nisoldipine (10 microM) blocks approximately 50%, while nifedipine (1 microM), diltiazem (20 microM), and verapamil (50 microM) each block one-third of the current. In contrast to its typical actions, BayK 8644 blocks the current by approximately 25%. Blockers of other Ca channel subtypes were also tested: omega-agatoxin IVA (200 nM) blocked only 13% of the Ca channel current, while omega-conotoxin GVIA (1 microM) blocked 84% of the current. Immnohistochemistry supported the presence of alpha1A, alpha1B, alpha1C, and alpha1D Ca channel subunits. Mapping of dihydropyridine-binding sites with DM-BODIPY revealed a distribution of channels over the entire membrane of the Muller cell with a higher density at the apical region. Overall, these observations suggest either the presence of a mix of L- and N-type Ca channels or a single, unconventional HVA Ca channel subtype sharing L- and N-type Ca channel characteristics.

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Section: Ca Channel Pharmacologymentioning

confidence: 80%

High‐voltage‐activated calcium channels in Müller cells acutely isolated from tiger salamander retina

Welch

Wood

Jollimore

et al. 2004

Glia

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“…Their function is modulated by Ca 2+ antagonists, which are classified into three classes with respect to their chemical structure (phenylalkylamines, dihydropyridines and benzothiazepines). Binding studies demonstrated cooperative interactions between Ca 2+ channel blockers from different groups (Porzig and Becker 1988;Striessnig et al 1993) as well as between agonists and antagonists (Kokubun et al 1986;Schreibmayer et al 1992). This has been taken as evidence for the existence of several non-identical but potentially overlapping binding sites for calcium channel ligands (Hockerman et al 1997;Striessnig et al 1998).…”

Section: Introductionmentioning

confidence: 97%

Interaction of three structurally distinct Ca2+ channel activators with single L-type Ca2+ channels

Lauven

Handrock

Müller

et al. 1999

Naunyn-Schmiedeberg's Arch Pharmacol

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The dihydropyridine S(-)-Bay K 8644 (Bay K), the benzoylpyrrole FPL 64176 (FPL) and the benzodiazocine CGP 48506 (CGP) are structurally unrelated L-type Ca2+ channels agonists. The aim of our study was to investigate whether these three drugs interact with different binding sites and thereby modulate the behaviour of L-type Ca2+ channels in a qualitatively different manner. Single-channel recordings were performed on CHO cells stably expressing the alpha1C-b subunit of the L-type Ca2+ channel. Mean open time and open probability were determined sweep by sweep and the effects of CGP (10(-4) M), Bay K (10(-6) M) and FPL (10(-6) M) were compared. All three compounds increased mean open time and open probability when applied alone. However, the gating pattern changes induced by each drug were qualitatively and quantitatively different. We also applied binary mixtures and analysed the resulting sweeps with respect to their gating pattern. The application of mixtures did result in a gating pattern not seen with any of the single drugs. The mixture of CGP and FPL led to a prolonged mean open time compared with each single drug. The mixture of Bay K and FPL exhibited an open probability lower than with each single drug. The mixture of CGP and Bay K increased the mean open time per sweep like Bay K, but the number of openings was similar to the level seen with CGP alone. These results cannot be explained by assuming alternative binding of the drugs to a single binding site. We therefore conclude that Bay K, CGP and FPL bind to different but interacting sites on the L-type Ca2+ channel.

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“…The P/Q‐type channel modulator R‐roscovitine exhibits both agonist and antagonist effects on P/Q‐type currents, which is determined by concentration and molecular conformation (Buraei and Elmslie, 2008). The L‐type calcium channel agonist Bay K 8644 enhances or suppresses cardiac calcium currents depending on the holding potential (Kass, 1987; Schreibmayer et al ., 1992). Such paradoxical regulation has also been shown for other dihydropyridines (Wei et al ., 1986).…”

Section: Discussionmentioning

confidence: 99%

A β‐amyloid oligomer directly modulates P/Q‐type calcium currents in Xenopus oocytes

Mezler

Barghorn

Groß

et al. 2012

British J Pharmacology

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BACKGROUND AND PURPOSEb-amyloid (Ab) oligomers have been implicated in the early pathophysiology of Alzheimer's disease (AD). While the precise nature of the molecular target has not been fully revealed, a number of studies have indicated that Ab oligomers modulate neuron-specific ion channels. We recently provided evidence that Ab oligomers suppress isolated P/Q-type calcium currents in cultured nerve cells. Using a heterologous expression system, we aimed to prove a direct effect on the membrane channel mediating such current. EXPERIMENTAL APPROACHThe effects of a synthetically generated Ab oligomer, Ab globulomer, were investigated on P/Q-type currents recorded from Xenopus laevis oocytes expressing the full P/Q-type calcium channel or the pore-forming subunit only. We also examined the effects of Ab globulomer on recombinant NMDA receptor currents. Finally, we compared the modulation by Ab globulomer with that induced by a synthetic monomeric Ab. KEY RESULTSAb globulomer directly and dose-dependently modulated P/Q-type calcium channels. A leftward shift of the current-voltage curve indicated that the threshold for channel opening was reduced. The effect of Ab globulomer was also present when only the a1A subunit of the normally tripartite channel was expressed. In contrast, the monomeric Ab had no effect on P/Q current. Also globulomer Ab had no effect on glutamate-induced NMDA currents. CONCLUSIONS AND IMPLICATIONSThe a1A subunit of the P/Q-type calcium channel is directly modulated by oligomeric Ab. Threshold reduction as well as an increase in current at synaptic terminals may facilitate vesicle release and could trigger excitotoxic events in the brains of patients with AD.

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Kinetic modulation of guinea‐pig cardiac L‐type calcium channels by fendiline and reversal of the effects of Bay K 8644

Cited by 14 publications

References 23 publications

High‐voltage‐activated calcium channels in Müller cells acutely isolated from tiger salamander retina

High‐voltage‐activated calcium channels in Müller cells acutely isolated from tiger salamander retina

Interaction of three structurally distinct Ca2+ channel activators with single L-type Ca2+ channels

A β‐amyloid oligomer directly modulates P/Q‐type calcium currents in Xenopus oocytes

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