A receptor for type I antiarrhythmic drugs associated with rat cardiac sodium channels.

Sheldon, Robert S.; Cannon, N J; Duff, Henry J.

doi:10.1161/01.res.61.4.492

Cited by 40 publications

(27 citation statements)

References 16 publications

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“…We have also tested Asn-406 because DI-S6 has been shown to contain the putative binding site for batrachotoxin (BTX) (16), an alkaloid neurotoxin. It has also been shown that batrachotoxin can be displaced from its binding site by LAs (15,19,20). Wang and Wang (20) demonstrated that three lysine point mutations in this region make the rat skeletal muscle Na ϩ channel ␣ subunit completely resistant to BTX.…”

Section: Discussionmentioning

confidence: 99%

Single point mutations affect fatty acid block of human myocardial sodium channel α subunit Na ⁺ channels

Xiao

Ke²,

Wang³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

115

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Suppression of cardiac voltage-gated Na ؉ currents is probably one of the important factors for the cardioprotective effects of the n-3 polyunsaturated fatty acids (PUFAs) against lethal arrhythmias. The ␣ subunit of the human cardiac Na ؉ channel (hH1␣) and its mutants were expressed in human embryonic kidney (HEK293t) cells. The effects of single amino acid point mutations on fatty acid-induced inhibition of the hH1 ␣ Na ؉ current (INa) were assessed. Eicosapentaenoic acid (EPA, C20:5n-3) significantly reduced I Na in HEK293t cells expressing the wild type, Y1767K, and F1760K of hH1␣ Na ؉ channels. The inhibition was voltage and concentration-dependent with a significant hyperpolarizing shift of the steady state of INa. In contrast, the mutant N406K was significantly less sensitive to the inhibitory effect of EPA. The values of the shift at 1, 5, and 10 M EPA were significantly smaller for N406K than for the wild type. Coexpression of the ␤1 subunit and N406K further decreased the inhibitory effects of EPA on I Na in HEK293t cells. In addition, EPA produced a smaller hyperpolarizing shift of the V1/2 of the steady-state inactivation in HEK293t cells coexpressing the ␤1 subunit and N406K. These results demonstrate that substitution of asparagine with lysine at the site of 406 in the domain-1-segment-6 region (D1-S6) significantly decreased the inhibitory effect of PUFAs on I Na, and coexpression with ␤1 decreased this effect even more. Therefore, asparagine at the 406 site in hH1␣ may be important for the inhibition by the PUFAs of cardiac voltage-gated Na ؉ currents, which play a significant role in the antiarrhythmic actions of PUFAs.human cardiac Na ϩ channel ͉ ␤1 subunit ͉ polyunsaturated fatty acids

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Section: Discussionmentioning

confidence: 99%

Single point mutations affect fatty acid block of human myocardial sodium channel α subunit Na ⁺ channels

Xiao

Ke²,

Wang³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

115

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“…Simiil cell of larly although the recovery from inhibition was comtrol (left) plete in both cases, the time required for recovery 1 (right). (Sheldon et al, 1987) to which scorpion toxin also binds (Catterall & Beress, 1978). It is also possible that scorpion toxin makes another channel carry the additional inward current.…”

Section: Discussionmentioning

confidence: 99%

Different time courses of the blockade of sodium current by lignocaine and SUN 1165 in single myocytes isolated from guinea‐pig atrium

Inomata

Ishihara

Akaike

1989

British J Pharmacology

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The time course of the blockade of sodium currents (INa) by the antiarrhythmic agents, lignocaine and SUN 1165, was studied in single myocytes isolated enzymatically from guinea‐pig atrium, by a new concentration‐jump termed as a ‘concentration‐clamp’ technique. This technique combines an intracellular perfusion and a rapid exchange of external solution surrounding the voltage‐clamped myocyte within 2 ms. Lignocaine (3.7 × 10−5 m to 3.7 × 10−4 M) inhibited the peak amplitude of INa in a concentration‐dependent fashion. It took 2 to 5 s to reach apparent steady‐state inhibition at the concentrations used. Complete recovery from the inhibition also took 2 to 5 s after washing out the agent. In contrast, the inhibitory effect of SUN 1165 (1 × 10−5 M) on the peak INa gradually progressed and reached a steady‐state level about 2 min after the start of drug‐application. The recovery required more than 10 min after washing out of the agent. In cardiomyocytes treated with scorpion toxin (5 μg ml−1), the inactivation of INa was greatly inhibited, resulting in the relatively persistent Na inward current (persistent INa) during the depolarizing pulse. Lignocaine (1.1 × 10−4 M) applied during the depolarizing pulse, reduced in a single‐exponential fashion the amplitude of the persistent INa in milliseconds. On the other hand, lignocaine applied several tens of milliseconds before the depolarizing pulse induced only a small reduction of the peak amplitude of the first persistent INa. When SUN 1165 (1 × 10−5 M) was applied during the depolarizing pulse, there was only a small instantaneous reduction of the amplitude of the persistent INa, although it did inhibit time‐dependently, the peak INa. Both agents accelerated the decay phase of the persistent INa in a time‐dependent manner. These results suggest that lignocaine and SUN 1165 may preferentially interact with the open‐state of the sodium channel rather than with the rested one, although SUN 1165 does so much more slowly.

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“…[3H]BTXB equilibrium binding Equilibrium binding assays were performed as described previously (3). Myocytes (6 x I0O cells/assay) in 50 Ml ofincubation buffer (MEM with 50 MM CaCl2 and 1% dialyzed BSA) were incubated with 1.3 MM sea anemone toxin (ATX), 0.13 mM tetrodotoxin (TTX), and various concentrations of [3H]BTXB for 55 min at 370C.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of the rat cardiac sodium channel by in vivo treatment with a class I antiarrhythmic drug.

Taouis¹,

Sheldon²,

Duff³

1991

J. Clin. Invest.

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Class I antiarrhythmic drugs inhibit the sodium channel by binding to a drug receptor associated with the channel. In this report we show that in vivo administration of the class I antiarrhythmic drug mexiletine to rats induces sodium channel upregulation in isolated cardiac myocytes. The number of sodium channels was assessed with a radioligand assay using the sodium channel-specific toxin j3HIbatrachotoxinin benzoate (PHIBTXB). The administration of mexiletine to rats induced a dose-dependent increase in PI-HBTXB total specific binding Invest. 1991. 88:375-378.)

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A receptor for type I antiarrhythmic drugs associated with rat cardiac sodium channels.

Cited by 40 publications

References 16 publications

Single point mutations affect fatty acid block of human myocardial sodium channel α subunit Na ⁺ channels

Single point mutations affect fatty acid block of human myocardial sodium channel α subunit Na ⁺ channels

Different time courses of the blockade of sodium current by lignocaine and SUN 1165 in single myocytes isolated from guinea‐pig atrium

Upregulation of the rat cardiac sodium channel by in vivo treatment with a class I antiarrhythmic drug.

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A receptor for type I antiarrhythmic drugs associated with rat cardiac sodium channels.

Cited by 40 publications

References 16 publications

Single point mutations affect fatty acid block of human myocardial sodium channel α subunit Na + channels

Single point mutations affect fatty acid block of human myocardial sodium channel α subunit Na + channels

Different time courses of the blockade of sodium current by lignocaine and SUN 1165 in single myocytes isolated from guinea‐pig atrium

Upregulation of the rat cardiac sodium channel by in vivo treatment with a class I antiarrhythmic drug.

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Single point mutations affect fatty acid block of human myocardial sodium channel α subunit Na ⁺ channels

Single point mutations affect fatty acid block of human myocardial sodium channel α subunit Na ⁺ channels