Voltage-dependent inhibition of the Na+,K+ pump by tetraethylammonium

Eckstein-Ludwig, Ursula; Rettinger, Jürgen; Vasilets, Larisa A.; Schwarz, Wolfgang

doi:10.1016/s0005-2736(98)00066-2

Cited by 16 publications

(24 citation statements)

References 31 publications

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“…Similar to a previous report on TEA (Eckstein-Ludwig et al, 1998), the 4-AP effect was voltage-dependent; stronger I pump inhibition was achieved at depolarized membrane potentials (Fig. 2).…”

Section: Suppression Of Nasupporting

confidence: 90%

Block of Na⁺,K⁺-ATPase and Induction of Hybrid Death by 4-Aminopyridine in Cultured Cortical Neurons

Wang¹,

Xiao²,

Yang³

et al. 2003

J Pharmacol Exp Ther

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Kϩ channel blockers such as 4-aminopyridine (4-AP) can be toxic to neurons; the cellular mechanism underlying the toxicity, however, is obscure. In cultured mouse cortical neurons, we tested the hypothesis that the toxic effect of 4-AP might result from inhibiting the Na ϩ ,K ϩ -ATPase (Na ϩ ,K ϩ -pump) and thereafter induction of a hybrid death of concomitant apoptosis and necrosis. The Na ϩ ,K ϩ -pump activity, monitored as whole-cell membrane currents, was markedly blocked by 4-AP in concentration-and voltage-dependent manners in low millimolar ranges. At similar concentrations, 4-AP induced a neuronal death sensitive to attenuation by the caspase inhibitor Z-VAD-FMK (Z-Val-Ala-Asp(OMe)-fluoromethyl ketone) or Ca 2ϩ chelator BAPTA-AM (1,2-bis(2-aminophenoxy)ethane-N,N,NЈ,NЈ-tetraacetic acid-acetoxymethyl ester). Electron microscopy confirmed hybrid ultrastructural features of coexisting apoptotic and necrotic components in same cells. We suggest that 4-AP is a potent antagonist of the Na ϩ ,K ϩ -ATPase and an inducer of the hybrid death of central neurons.Aminopyridines, particularly 4-aminopyridine (4-AP), have been investigated as a means of beneficial symptomatic treatment in a variety of neurological conditions of demyelination diseases including multiple sclerosis, myasthenia gravis, and spinal cord injury (Murray and Newsom-Davis, 1981; Jones et al

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Section: Suppression Of Nasupporting

confidence: 90%

Block of Na⁺,K⁺-ATPase and Induction of Hybrid Death by 4-Aminopyridine in Cultured Cortical Neurons

Wang¹,

Xiao²,

Yang³

et al. 2003

J Pharmacol Exp Ther

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“…6). The reported competitive behavior was already found earlier, 33,34 and may be explained by the space-filling, hampering size of TEA + molecules (Fig. S2).…”

Section: Discussionsupporting

confidence: 78%

“…The inhibitory effect of both compounds on K + binding has been already observed earlier. [33][34][35] A third kind of "interaction" was found for DMA + . According to the missing effect on the RH421 fluorescence ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…[29][30][31][32] TEA + inhibited the Na,KATPase in voltage-independent manner. [33][34][35] In contrast, other quaternary amines such as BTEA + showed a voltage-dependent inhibition and this voltage sensitivity could be used to test their access to the binding sites as function of their size. [35][36][37][38] The latter approach was used preferentially with cardiac myocytes, and the voltage dependence of the Na,K-ATPase specific currents through the membrane were studied in the presence of those organic amines which provide evidence of the extracellular access channel, and in addition introduced a new species of voltage-dependent inhibitors of the sodium pump.…”

Section: Introductionmentioning

confidence: 99%

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Probing the Extracellular Access Channel of the Na,K-ATPase

Gradinaru

Apell

2015

Biochemistry

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When the Na,K-ATPase pumps at each turnover two K(+) ions into the cytoplasm, this translocation consists of several reaction steps. First, the ions diffuse consecutively from the extracellular phase through an access pathway to the binding sites where they are coordinated. In the next step, the enzyme is dephosphorylated and the ions are occluded inside the membrane domain. The subsequent transition to the E1 conformation produces a deocclusion of the binding sites to the cytoplasmic side of the membrane and allows in the last steps ion dissociation and diffusion to the aqueous phase. The interaction and competition of K(+) with various quaternary organic ammonium ions have been used to gain insight into the molecular mechanism of the ion binding process from the extracellular side in the P-E2 conformation of the enzyme. Using the electrochromic styryl dye RH421, evidence has been obtained that the access pathway consists of a wide and water-filled funnel-like part that is accessible also for bulky cations such as the benzyltriethylammonium ion, and a narrow part that permits passage only of small cations such as K(+) and NH4(+) in a distinct electrogenic way. Benzyltriethylammonium ions inhibit K(+) binding in a competitive manner that can be explained by a stopper-like function at the interface between the wide and narrow parts of the access pathway. In contrast to other quaternary organic ammonium ions, benzyltriethylammonium ions show a specific binding to the ion pump in a position inside the access pathway where it blocks effectively the access to the binding sites.

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“…First, classical Kv channel blockers such as TEA and 4-AP have actions on other K + -handling protein molecules such as Na + -K + -ATPases (Eckstein-Ludwig et al 1998;Wang et al 2003). The side effects would limit the use of them as therapeutic agents in vivo.…”

Section: Practical Considerations and Future Prospectsmentioning

confidence: 99%

Voltage-gated K+ channel modulators as neuroprotective agents

Leung

2010

Life Sciences

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Voltage-dependent inhibition of the Na+,K+ pump by tetraethylammonium

Cited by 16 publications

References 31 publications

Block of Na⁺,K⁺-ATPase and Induction of Hybrid Death by 4-Aminopyridine in Cultured Cortical Neurons

Block of Na⁺,K⁺-ATPase and Induction of Hybrid Death by 4-Aminopyridine in Cultured Cortical Neurons

Probing the Extracellular Access Channel of the Na,K-ATPase

Voltage-gated K+ channel modulators as neuroprotective agents

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Voltage-dependent inhibition of the Na+,K+ pump by tetraethylammonium

Cited by 16 publications

References 31 publications

Block of Na+,K+-ATPase and Induction of Hybrid Death by 4-Aminopyridine in Cultured Cortical Neurons

Block of Na+,K+-ATPase and Induction of Hybrid Death by 4-Aminopyridine in Cultured Cortical Neurons

Probing the Extracellular Access Channel of the Na,K-ATPase

Voltage-gated K+ channel modulators as neuroprotective agents

Contact Info

Product

Resources

About

Block of Na⁺,K⁺-ATPase and Induction of Hybrid Death by 4-Aminopyridine in Cultured Cortical Neurons

Block of Na⁺,K⁺-ATPase and Induction of Hybrid Death by 4-Aminopyridine in Cultured Cortical Neurons