Very high affinity interaction of DPI 201‐106 and BDF 8784 enantiomers with the phenylalkylamine‐sensitive Ca<sup>2+</sup>‐channel in <i>Drosophila</i> head membranes

Glossmann, Hartmut; Zech, Christina; Striessnig, Jörg; Staudinger, Robert; Hall, Linda M.; Greenberg, Robert M.; Armah, Benjamin

doi:10.1111/j.1476-5381.1991.tb12193.x

Cited by 12 publications

(5 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One channel is highly sensitive to PAs, but insensitive to micromolar concentrations of DHPs, whereas two other channels proved DHP-sensitive but PA-insensitive. These observations ®t well with radioligand binding studies of the Drosophila head, showing that PA-binding sites lack allosterically coupled DHP receptors (Pauron et al, 1987;Glossmann et al, 1991). While vertebrate L-channels bind DHPs, PAs and BTZs on the same subunit, in Drosophila a particular channel appears to have binding sites for either PAs or DHPs, but not for both.…”

Section: Discussionsupporting

confidence: 76%

See 1 more Smart Citation

Presynaptic calcium‐channel currents in normal and csp mutant Drosophila peptidergic terminals

Morales

Ferrús

Martínez-Padrón

1999

Eur J of Neuroscience

View full text Add to dashboard Cite

The study of regulated vesicle exocytosis, which underlies neurotransmitter and neuropeptide release, has benefited from a convergence of several independent approaches. These include the use of genetically tractable organisms and model preparations that allow a direct characterization of presynaptic ionic currents. Aiming for a comprehensive analysis of release, we had already developed a Drosophila preparation in which electrophysiological recordings from peptidergic terminals are feasible. Here, we report on the characterization of the Ca2+-channel currents present in these terminals. With Ba2+ as the charge carrier, the presynaptic membrane expresses a current type with high-activation threshold and little inactivation. This current is blocked by verapamil and diltiazem at micromolar concentrations, it is relatively insensitive to nifedipine and completely resistant to non-L-type Ca2+-channel antagonists. As a comparison, we also analysed the pharmacology of high-threshold Ba+2 currents on muscle fibres. A high-activation threshold Ca2+-channel current is also present in muscle fibres, albeit with a distinct pharmacological profile. Thus, peptidergic terminals and muscle fibres exhibit different subtypes of voltage-gated Ca2+ channels. The putative role of cysteine string protein (CSP) as a neuronal Ca2+-channel modulator was tested by examining the peptidergic presynaptic current in csp null mutants. We show that CSP is expressed in peptidergic boutons and abolished in the mutant. Direct recordings, under conditions that inhibit calcium influx into glutamatergic terminals, show that Ca2+-currents in peptidergic csp terminals are entirely normal. This result indicates that CSP is not a generic Ca2+-channel modulator and it might perform different functions in fast versus slow forms of release.

show abstract

Section: Discussionsupporting

confidence: 76%

“…These observations fit well with radioligand binding studies of the Drosophila head, showing that PA‐binding sites lack allosterically coupled DHP receptors (Pauron et al . 1987; Glossmann et al . 1991).…”

Section: Discussionmentioning

confidence: 99%

Presynaptic calcium‐channel currents in normal and csp mutant Drosophila peptidergic terminals

Morales

Ferrús

Martínez-Padrón

1999

Eur J of Neuroscience

View full text Add to dashboard Cite

show abstract

“…Analogues I and VI had inhibitory activity that was similar against calcium and sodium channels, but, where other comparisons could be drawn, the BZPs generally showed weaker inhibitory activity against calcium channels. It is of interest to note that other therapeutic diphenylpiperidines, such as lifarizine, DPI 201‐106 and flunarizine have also been reported to block both sodium and calcium channels 6–10. 30…”

Section: Discussionmentioning

confidence: 99%

“…The present investigation aimed to provide, for the first time, a detailed analysis of the mechanism by which BZPs interact with mammalian brain. In this work, primary emphasis was given to examining potential effects of BZPs at sodium and calcium channels in view of their dihydropyrazole‐like symptomology in insects and some structural resemblance to diphenylpiperazines of therapeutic potential which are known to interact with both complexes 6–10…”

Section: Introductionmentioning

confidence: 99%

Insecticidal arylalkylbenzhydrolpiperidines: novel inhibitors of voltage‐sensitive sodium and calcium channels in mammalian brain

Leong¹,

Bloomquist²,

Bempong³

et al. 2001

Pest Management Science

View full text Add to dashboard Cite

Using preparations derived from whole mouse brain, we have demonstrated that insecticidal arylalkylbenzhydrolpiperidines inhibit the depolarization of synaptoneurosomes as measured by rhodamine 6G fluorescence and block 22Na+ uptake into synaptosomes, when veratridine is used as the activator. These insecticides also have the ability to potently displace the binding of [3H]batrachotoxinin A 20-alpha-benzoate ([3H]BTX-B) to neuronal sodium channels in a concentration-dependent manner. The study compounds can be classified as competitive inhibitors of radioligand binding, since they decrease the affinity of [3H]BTX-B for site 2 without affecting the concentration of sites labelled by this radioligand. Our kinetic analyses revealed that at its IC50, the 4-carbomethoxyaminobenzyl-piperidine analogue reduces the rate of association of [3H]BTX-B with site 2, whereas higher concentrations were required to accelerate dissociation of the [3H]BTX-B:sodium channel complex. These results indicate an ability to interact with both non-activated and persistently activated states of the voltage-sensitive sodium channel, but higher affinity for the former. Such a profile also implies that inhibition of [3H]BTX-B binding to site 2 occurs via an allosteric mechanism. In addition, arylalkylbenzhydrolpiperidines interact with presynaptic voltage-sensitive calcium channels, since we demonstrate that they inhibit increases in [free Ca++] and 45Ca++ uptake when evoked by high KC1 concentration in mouse brain synaptosomal preparations. Such effects generally occur at concentrations that are higher than those required to inhibit sodium channels. Blockade of sodium and calcium channels may therefore contribute to the in vivo neurological effects observed in rodents exposed to these insecticides.

show abstract

“…through interactions at the benzothiazepine receptor site at the L-channel (King et al, 1988;Triggle et al, 1989;Glossman et al, 1991). Structurally, tetrandrine is unique among the known chemical classes of calcium entry blockers (Triggle et al, 1989;Dong et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Investigations of the dual contractile/relaxant properties showed by antioquine in rat aorta

Ivorra

Lugnier²,

Catret

et al. 1993

British J Pharmacology

View full text Add to dashboard Cite

1 In the present study we assessed the activity of antioquine, a bisbenzyltetrahydroisoquinoline alkaloid isolated from Pseudoxandra sclerocarpa, by examining its effects on 3 Paradoxically, at the highest concentration tested (300 gM) antioquine induced a contractile response of similar magnitude in the presence and absence of extracellular calcium, at 37°C. This activity was greatly attenuated at 25°C. Antioquine-induced contractions were not inhibited by prazosin (0.1 JIM), nifedipine (1 gM) or diltiazem (100 gM). On the contrary, prazosin and nifedipine slightly increased the contractions in the presence of extracellular calcium. Papaverine (100 jiM) partially inhibited the contractile response to antioquine both in the presence and absence of extracellular calcium. 4 At 25°C, in Ca2+-free solution, antioquine (300 jiM) did not modify the contractile response (phasic and tonic) evoked by noradrenaline, but increased the phasic contraction induced by caffeine. At 37°C, the contraction elicited by antioquine made it impossible to observe the noradrenaline-induced one. Antioquine showed affinity for the [3H]-prazosin binding site and for the [3H]-(+)-cis-diltiazembinding site of the Ca2+-channel receptor complex, but had no effect at the dihydropyridine binding site in rat cerebral cortex.6 Antioquine weakly inhibited some PDE forms isolated from bovine aorta: a CaM-PDE (PDE I) which preferentially hydrolyzes cyclic GMP and is activated by calmodulin, and a rolipram-sensitive cyclic AMP-PDE (PDE IV) which hydrolyzed cyclic AMP. Antioquine did not exert any inhibitory effect on the other forms of PDE, a cyclic GMP selective form (PDE V) and a low Km cyclic AMP-PDE that is inhibited by cyclic GMP (CGI-PDE, PDE III). 7 The present work provides evidence that antioquine has properties both as a calcium entry blocker (possibly through the benzothiazepine recognition site in the calcium channel) and as a contractile agent.Its mechanism of action as a contractile agent is not related to Ca2+-entry and is hypothetically similar to that of calyculin-A or okadaic acid. The possible involvement of a-adrenoceptors in this paradoxical effect cannot be excluded. The rigidity of the molecule provides an interesting model for analyzing this contractile mechanism and the intracellular processes involved.

show abstract

Very high affinity interaction of DPI 201‐106 and BDF 8784 enantiomers with the phenylalkylamine‐sensitive Ca²⁺‐channel in Drosophila head membranes

Cited by 12 publications

References 25 publications

Presynaptic calcium‐channel currents in normal and csp mutant Drosophila peptidergic terminals

Presynaptic calcium‐channel currents in normal and csp mutant Drosophila peptidergic terminals

Insecticidal arylalkylbenzhydrolpiperidines: novel inhibitors of voltage‐sensitive sodium and calcium channels in mammalian brain

Investigations of the dual contractile/relaxant properties showed by antioquine in rat aorta

Contact Info

Product

Resources

About

Very high affinity interaction of DPI 201‐106 and BDF 8784 enantiomers with the phenylalkylamine‐sensitive Ca2+‐channel in Drosophila head membranes

Cited by 12 publications

References 25 publications

Presynaptic calcium‐channel currents in normal and csp mutant Drosophila peptidergic terminals

Presynaptic calcium‐channel currents in normal and csp mutant Drosophila peptidergic terminals

Insecticidal arylalkylbenzhydrolpiperidines: novel inhibitors of voltage‐sensitive sodium and calcium channels in mammalian brain

Investigations of the dual contractile/relaxant properties showed by antioquine in rat aorta

Contact Info

Product

Resources

About

Very high affinity interaction of DPI 201‐106 and BDF 8784 enantiomers with the phenylalkylamine‐sensitive Ca²⁺‐channel in Drosophila head membranes