Selective activation of Ca2+ -dependent K+ channels by novel benzimidazolone

Olesen, Søren‐Peter; Munch, Ellen; Moldt, P.; Drejer, Jørgen

doi:10.1016/0014-2999(94)90442-1

Cited by 286 publications

(213 citation statements)

References 25 publications

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“…Therefore, we tested whether or not expression of kcnma1 in C. elegans conferred sensitivity to known agonists of this channel, as might be predicted from the observed functional rescue. We tested the effects of an activator of mammalian BK channels, NS1619 (Olesen et al, 1994), on locomotion of wild-type and slo-1(js379)-, js379;pslo-1::slo-1-, and js379;pslo-1::kcnma1-expressing strains of C. elegans. NS1619 is used widely for its ability to relax smooth muscle (Olesen et al, 1994) and inhibit neuronal activity (Lee et al, 1995) by a selective activation of calcium-activated BK channels.…”

Section: Structural Comparison Of Slo-1 and Kcnma1mentioning

confidence: 99%

“…We tested the effects of an activator of mammalian BK channels, NS1619 (Olesen et al, 1994), on locomotion of wild-type and slo-1(js379)-, js379;pslo-1::slo-1-, and js379;pslo-1::kcnma1-expressing strains of C. elegans. NS1619 is used widely for its ability to relax smooth muscle (Olesen et al, 1994) and inhibit neuronal activity (Lee et al, 1995) by a selective activation of calcium-activated BK channels. NS1619 was chosen for these experiments as it can act at mammalian channels in the absence of accessory ␤ subunits (Zakharov et al, 2005).…”

Section: Structural Comparison Of Slo-1 and Kcnma1mentioning

confidence: 99%

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Selective Toxicity of the Anthelmintic Emodepside Revealed by Heterologous Expression of Human KCNMA1 inCaenorhabditis elegans

Crisford¹,

Murray²,

O’Connor³

et al. 2011

Mol Pharmacol

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Emodepside is a resistance-breaking anthelmintic of a new chemical class, the cyclooctadepsipeptides. A major determinant of its anthelmintic effect is the calcium-activated potassium channel SLO-1. SLO-1 belongs to a family of channels that are highly conserved across the animal phyla and regulate neurosecretion, hormone release, muscle contraction, and neuronal network excitability. To investigate the selective toxicity of emodepside, we performed transgenic experiments in which the nematode SLO-1 channel was swapped for a mammalian ortholog, human KCNMA1. Expression of either the human channel or Caenorhabditis elegans slo-1 from the native slo-1 promoter in a C. elegans slo-1 functional null mutant rescued behavioral deficits that otherwise resulted from loss of slo-1 signaling. However, worms expressing the human channel were 10-to 100-fold less sensitive to emodepside than those expressing the nematode channel. Strains expressing the human KCNMA1 channel were preferentially sensitive to the mammalian channel agonists NS1619 and rottlerin. In the C. elegans pharyngeal nervous system, slo-1 is expressed in neurons, not muscle, and cell-specific rescue experiments have previously shown that emodepside inhibits serotonin-stimulated feeding by interfering with SLO-1 signaling in the nervous system. Here we show that ectopic overexpression of slo-1 in pharyngeal muscle confers sensitivity of the muscle to emodepside, consistent with a direct interaction of emodepside with the channel. Taken together, these data predict an emodepside-selective pharmacophore harbored by SLO-1. This has implications for the development of this drug/ target interface for the treatment of helminth infections.

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Section: Structural Comparison Of Slo-1 and Kcnma1mentioning

confidence: 99%

Section: Structural Comparison Of Slo-1 and Kcnma1mentioning

confidence: 99%

Selective Toxicity of the Anthelmintic Emodepside Revealed by Heterologous Expression of Human KCNMA1 inCaenorhabditis elegans

Crisford¹,

Murray²,

O’Connor³

et al. 2011

Mol Pharmacol

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“…Nor-BNI (Portoghese et al, 1994), a selective antagonist of k-ORs, was used to block the effect of k-OR stimulation at 5 mM (Schoffelmeer et al, 1997;Wang et al, 2001a). Pax (1 mM) and NS1619 (10 mM), which have been shown to inhibit and open the K Ca channel, respectively (Olesen et al, 1994;Gribkoff et al, 1996;Xu et al, 2002;Shintani et al, 2004;Cao et al, 2005;Sato et al, 2005), were used to block and activate the K Ca channel, at doses used in a previous study (Xu et al, 2002;Cao et al, 2005). PMA (0.1 mM) and Che or GF (10 mM), PKC activator and inhibitors, respectively, were used at the doses used by Liang (1997) and Ahmet et al (2000).…”

Section: Chemicalsmentioning

confidence: 99%

The K_Ca channel as a trigger for the cardioprotection induced by kappa‐opioid receptor stimulation – its relationship with protein kinase C

Cao

Chen

Wong

2005

British J Pharmacology

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1 We first determined whether the cardioprotection resulting from kappa opioid receptor (k-OR) stimulation was blocked by the K Ca channel inhibitor, paxilline (Pax), administered before or during ischaemic insults in vitro. 2 In isolated rat hearts, 30 min of ischaemia and 120 min of reperfusion induced infarction and increased lactate dehydrogenase (LDH) release. In isolated ventricular myocytes subjected to 5 min of metabolic inhibition and anoxia followed by 10 min of reperfusion, the percentage of live cells and the amplitude of the electrically induced intracellular Ca 2 þ ([Ca 2 þ ] i ) transient decreased, while diastolic [Ca 2 þ ] i increased. Pretreatment with 10 mM U50,488H, a k-OR agonist, attenuated the undesirable effects of ischaemic insults in both preparations. The beneficial effects of k-OR stimulation, that were abolished by 5 mM nor-BNI, a k-OR antagonist, were also abolished by 1 mM Pax administered before ischaemic insults or 20 mM atractyloside, an opener of the mitochondrial permeability transition pore. 3 Activation of protein kinase C (PKC) with 0.1 mM phorbol 12-myristate 13-acetate decreased the infarct size and LDH release in isolated rat hearts subjected to ischaemia/reperfusion, and these effects were abolished by blockade of PKC with its inhibitors, 10 mM GF109203X or 5 mM chelerythrine, and more importantly by 1 mM Pax. On the other hand, the cardioprotective effects of opening the K Ca channel with 10 mM NS1619 were not altered by either PKC inhibitor. 4 In conclusion, the high-conductance K Ca channel triggers cardioprotection induced by k-OR stimulation that involves inhibition of MPTP opening. The K Ca channel is located downstream of PKC.

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“…These observations are thus consistent with the findings of the present study and of Lawson et al (1993) that the relaxation of guinea-pig trachealis by BRL55834 was partially glibenclamide-resistant, especially when tissues were exposed to BRL55834 prior to glibenclamide. There was, however, a marked contrast between the glibenclamide-insensitive current induced by BRL55834 and that stimulated by NS1619, the opener of BKca Olesen et al, 1994). IBK(Ca) induced by NS1619 had an activation threshold close to 0 mV and showed marked outward rectification whereas the I-V relationship for the glibenclamide-insensitive current produced by BRL55834 showed none of these characteristics and could be fitted by the Goldman-Hodgkin-Katz equation.…”

Section: Effects Of Brl5s834 On K-currents In Bovine Trachealismentioning

confidence: 88%

Effects of BRL55834 in rat portal vein and bovine trachea: evidence for the induction of a glibenclamide‐resistant, ATP‐sensitive potassium current

Edwards

Schneider

Niederste-Hollenberg

et al. 1995

British J Pharmacology

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1 The effects of the benzopyran K-channel opener, BRL55834, on mechanical activity in bovine trachealis and rat portal vein were studied together with membrane currents in freshly-isolated single cells derived from these tissues. 2 BRL55834 (3 nM-1 iM) produced a concentration-dependent relaxation of bovine trachealis precontracted with 100 gM histamine and reduced the spontaneous mechanical activity of rat portal veins, effects which were antagonized by glibenclamide (1 -10 gM) but were not reversible on washing. In contrast, charybdotoxin (250 nM) did not modify the spasmolytic effect of BRL55834 in bovine trachealis.3 BRL55834 (10 nM-10 gM) did not relax segments of bovine trachealis precontracted with 80 mM KCl.4 In some freshly-isolated single cells from bovine trachealis held at -10 mV, BRL55834 (3 giM) induced a time-independent outward K-current which was partially resistant to inhibition by glibenclamide (10 giM). In other cells, a very noisy, outwardly-rectifying and charybdotoxin-sensitive current developed in the presence of BRL55834 (3 giM) and in time-matched control cells. 5 In freshly-isolated single cells from rat portal vein held at -10 mV, BRL55834 (3 gM) induced a timeand calcium-independent outward K-current which was partially resistant (approximately 25% inhibition at + 40 mV) to subsequent inhibition by glibenclamide (10 gM). In contrast, levcromakalim induced a time-independent outward K-current which was completely inhibited by glibenclamide 10 gM. 6 With the non-hydrolysable ATP analogue, AMP-PCP (5 mM), in the pipette, the ability of BRL55834 to induce a time-independent K-current in portal vein cells was markedly reduced (approximately 80% inhibition at + 40 mV) whereas the effects of 10 gM levcromakalim were totally inhibited. 7 The glibenclamide-resistant current component induced by BRL55834 was totally inhibited by phentolamine (100 gM), a concentration that had no effect on the peak current (IBK(Ca)) induced by NS1619 (33 giM).8 Stationary fluctuation analysis of the noise associated with the glibenclamide-insensitive K-current induced by BRL55834 in rat portal vein cells indicated that the unitary current flowing through the underlying channels was 0.26 pA at -10 mV, a value inconsistent with the involvement of BKca.9 It is concluded that the relaxations of both bovine trachea and rat portal vein produced by BRL55834 are associated with the opening of K-channels. These are probably identical to the ATPsensitive K-channel opened by levcromakalim, although the involvement of an additional K-channel cannot be excluded. The reduced sensitivity of the BRL55834-induced changes to glibenclamide and to AMP-PCP may result from avid binding of BRL55834 to its site of action.

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Selective activation of Ca2+ -dependent K+ channels by novel benzimidazolone

Cited by 286 publications

References 25 publications

Selective Toxicity of the Anthelmintic Emodepside Revealed by Heterologous Expression of Human KCNMA1 inCaenorhabditis elegans

Selective Toxicity of the Anthelmintic Emodepside Revealed by Heterologous Expression of Human KCNMA1 inCaenorhabditis elegans

The K_Ca channel as a trigger for the cardioprotection induced by kappa‐opioid receptor stimulation – its relationship with protein kinase C

Effects of BRL55834 in rat portal vein and bovine trachea: evidence for the induction of a glibenclamide‐resistant, ATP‐sensitive potassium current

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Selective activation of Ca2+ -dependent K+ channels by novel benzimidazolone

Cited by 286 publications

References 25 publications

Selective Toxicity of the Anthelmintic Emodepside Revealed by Heterologous Expression of Human KCNMA1 inCaenorhabditis elegans

Selective Toxicity of the Anthelmintic Emodepside Revealed by Heterologous Expression of Human KCNMA1 inCaenorhabditis elegans

The KCa channel as a trigger for the cardioprotection induced by kappa‐opioid receptor stimulation – its relationship with protein kinase C

Effects of BRL55834 in rat portal vein and bovine trachea: evidence for the induction of a glibenclamide‐resistant, ATP‐sensitive potassium current

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The K_Ca channel as a trigger for the cardioprotection induced by kappa‐opioid receptor stimulation – its relationship with protein kinase C