Selective blockade of the delayed rectifier potassium current by tacrine inDrosophila

Kraliz, Derek; Singh, Satpal

doi:10.1002/(sici)1097-4695(199701)32:1<1::aid-neu1>3.0.co;2-d

Cited by 30 publications

(3 citation statements)

References 27 publications

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“…Quinidine blocks Drosophila Shab channels in a highly selective manner (47)(48)(49). If celecoxib induced arrhythmia by inhibiting these channels, then quinidine also would induce arrhythmia.…”

Section: A) Although 1 M Celecoxib Did Not Affect Rhythm In All Casesmentioning

confidence: 99%

Inhibition of Delayed Rectifier Potassium Channels and Induction of Arrhythmia

Frolov

Berim

Singh

2008

Journal of Biological Chemistry

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Selective inhibitors of cyclooxygenase-2 (COX-2), such as rofecoxib (Vioxx), celecoxib (Celebrex), and valdecoxib (Bextra), have been developed for treating arthritis and other musculoskeletal complaints. Selective inhibition of COX-2 over COX-1 results in preferential decrease in prostacyclin production over thromboxane A2 production, thus leading to less gastric effects than those seen with nonselective COX inhibitors such as acetylsalicylic acid (aspirin). Here we show a novel effect of celecoxib via a mechanism that is independent of COX-2 inhibition. The drug inhibited the delayed rectifier (Kv2) potassium channels from Drosophila, rats, and humans and led to pronounced arrhythmia in Drosophila heart and arrhythmic beating of rat heart cells in culture. These effects occurred despite the genomic absence of cyclooxygenases in Drosophila and the failure of acetylsalicylic acid, a potent inhibitor of both COX-1 and COX-2, to inhibit rat Kv2.1 channels. A genetically null mutant of Drosophila Shab (Kv2) channels reproduced the cardiac effect of celecoxib, and the drug was unable to further enhance the effect of the mutation. These observations reveal an unanticipated effect of celecoxib on Drosophila hearts and on heart cells from rats, implicating the inhibition of Kv2 channels as the mechanism underlying this effect.Selective COX-2 2 inhibitors, or coxibs, were developed for use as nonsteroidal anti-inflammatory drugs without adverse gastric effects (1, 2). Gastric effects of nonselective cyclooxygenase inhibitors, such as acetylsalicylic acid (aspirin), arise in main part from inhibition of cyclooxygenase-1. A selective inhibition of COX-2 by coxibs helps avoid these effects (3, 4); however, adverse cardiovascular effects complicate the use of coxibs (5-7). These effects of coxibs have been attributed to a reduction in antithrombotic, COX-2-derived prostacyclin without a reduction in prothrombotic, COX-1-derived platelet thromboxane. This shifts the balance toward a prothrombotic state resulting in clot formation (7).The adverse effects of drugs like celecoxib arising from their selective inhibition of COX-2 is currently the topic of intense discussion (7,8). We now show that celecoxib can have additional, heretofore unanticipated effects on Drosophila hearts and rat heart cells via a pathway independent of cyclooxygenase inhibition. At low micromolar concentrations, celecoxib reduced heart rate and induced pronounced arrhythmia in Drosophila hearts. A similar effect was observed in rat cardiomyocytes in culture in which the drug reduced the beating rate in clusters of cells and made the beating arrhythmic. These effects were not mediated via cyclooxygenase inhibition but involved inhibition of the voltage-activated delayed rectifier K ϩ channels (Kv2) by the drug. These observations reveal a new molecular mechanism underlying the effects of celecoxib that may operate in addition to its prothrombotic influence. The data also raise the possibility of effects on other tissues that express Kv2 channels. EXPERIM...

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Section: A) Although 1 M Celecoxib Did Not Affect Rhythm In All Casesmentioning

confidence: 99%

Inhibition of Delayed Rectifier Potassium Channels and Induction of Arrhythmia

Frolov

Berim

Singh

2008

Journal of Biological Chemistry

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“…As two major classes of K v currents in central neurons, I K(A) channels played crucial roles in regulating neuronal excitability by modulating action potential firing frequency and slowing the rate of depolarization, whereas I K(DR) channels function to promote the onset of repolarization and maintain the baseline membrane potential. In pharmacology, it has been found AChE inhibitors could affect central outward K + channels 32 , such as tacrine, donepezil, which inhibited I K(A) in rat hippocampal neurons 33 and/or I K(DR) in the larval muscles of Drosophila 34 . Ca 2+ -dependent K + currents also had been reported to underlie the mechanism of hyperexcitability induced by paraoxon in snail neurons 8 .…”

Section: Resultsmentioning

confidence: 99%

Discovery and identification of O, O-diethyl O-(4-(5-phenyl-4, 5-dihydroisoxazol-3-yl) phenyl) phosphorothioate (XP-1408) as a novel mode of action of organophosphorus insecticides

Zeng

Yan

Wang

et al. 2017

Sci Rep

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Organophosphorus (OP) insecticides play an important role in pest control. Many OP insecticides have been removed from the market because of their high toxicity to humans. We designed and synthesized a new OP insecticide with the goal of providing a low cost, and less toxic insecticide. The mode of action of O, O-diethyl O-(4-(5-phenyl-4, 5-dihydroisoxazol-3-yl) phenyl) phosphorothioate (XP-1408) was studied in Drosophila melanogaster. Bioassays showed that XP-1408 at a concentration of 50 mg/L delayed larval development. Molecular docking into Drosophila acetylcholinesterase (AChE) and voltage-gated sodium channels suggested that XP-1408 fitted into their active sites and could be inhibitory. Whole-cell patch clamp recordings indicated that XP-1408 exhibited synergistic effects involving the inhibition of cholinergic synaptic transmission and blockage of voltage-gated potassium (Kv) channels and sodium (Nav) channels. In conclusion, the multiple actions of XP-1408 rendered it as a lead compound for formulating OP insecticides with a novel mode of action.

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“…Electrophysiology-Body wall muscle 12 (22, 23) of mature third instar larvae of wild-type (CS) 2 and various mutant strains was used for the two-electrode voltage clamp experiments as described previously (24). Ca 2ϩ -free recording solution contained 77.5 mM NaCl, 115 mM sucrose, 5 mM KCl, 0.5 mM EGTA, 20 mM MgCl 2 , 5 mM Trehalose, 2.5 mM NaHCO 3 , and 5 mM HEPES (pH 7.1) (25,26).…”

Section: Isolation Of 9gmentioning

confidence: 99%

Mutational Analysis of the Shab-encoded Delayed Rectifier K+ Channels in Drosophila

Hegde¹,

Gu²,

Dong³

et al. 1999

Journal of Biological Chemistry

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K؉ currents in Drosophila muscles have been resolved into two voltage-activated currents (I A and I K ) and two Ca 2؉ -activated currents (I CF and I CS ). Mutations that affect I A (Shaker) and I CF (slowpoke) have helped greatly in the analysis of these currents and their role in membrane excitability. Lack of mutations that specifically affect channels for the delayed rectifier current (I K ) has made their genetic and functional identity difficult to elucidate. With the help of mutations in the Shab K ؉ channel gene, we show that this gene encodes the delayed rectifier K ؉ channels in Drosophila. Three mutant alleles with a temperature-sensitive paralytic phenotype were analyzed. Analysis of the ionic currents from mutant larval body wall muscles showed a specific effect on delayed rectifier K ؉ current (I K ). Two of the mutant alleles contain missense mutations, one in the aminoterminal region of the channel protein and the other in the pore region of the channel. The third allele contains two deletions in the amino-terminal region and is a null allele. These observations identity the channels that carry the delayed rectifier current and provide an in vivo physiological role for the Shab-encoded K ؉ channels in Drosophila. The availability of mutations that affect I K opens up possibilities for studying I K and its role in larval muscle excitability.

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Selective blockade of the delayed rectifier potassium current by tacrine inDrosophila

Cited by 30 publications

References 27 publications

Inhibition of Delayed Rectifier Potassium Channels and Induction of Arrhythmia

Inhibition of Delayed Rectifier Potassium Channels and Induction of Arrhythmia

Discovery and identification of O, O-diethyl O-(4-(5-phenyl-4, 5-dihydroisoxazol-3-yl) phenyl) phosphorothioate (XP-1408) as a novel mode of action of organophosphorus insecticides

Mutational Analysis of the Shab-encoded Delayed Rectifier K+ Channels in Drosophila

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