Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels

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Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels. / Pless, Stephan Alexander; Galpin, Jason D; Frankel, Adam; Ahern, Christopher A.

In: Nature Communications, Vol. 2, 2011, p. 351.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Pless, SA, Galpin, JD, Frankel, A & Ahern, CA 2011, 'Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels', Nature Communications, vol. 2, pp. 351. https://doi.org/10.1038/ncomms1351

APA

Pless, S. A., Galpin, J. D., Frankel, A., & Ahern, C. A. (2011). Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels. Nature Communications, 2, 351. https://doi.org/10.1038/ncomms1351

Vancouver

Pless SA, Galpin JD, Frankel A, Ahern CA. Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels. Nature Communications. 2011;2:351. https://doi.org/10.1038/ncomms1351

Author

Pless, Stephan Alexander ; Galpin, Jason D ; Frankel, Adam ; Ahern, Christopher A. / Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels. In: Nature Communications. 2011 ; Vol. 2. pp. 351.

Bibtex

@article{fabe0296751a4045ad8dcf2a31037d49,
title = "Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels",
abstract = "Cardiac sodium channels are established therapeutic targets for the management of inherited and acquired arrhythmias by class I anti-arrhythmic drugs (AADs). These drugs share a common target receptor bearing two highly conserved aromatic side chains, and are subdivided by the Vaughan-Williams classification system into classes Ia-c based on their distinct effects on the electrocardiogram. How can these drugs elicit distinct effects on the cardiac action potential by binding to a common receptor? Here we use fluorinated phenylalanine derivatives to test whether the electronegative surface potential of aromatic side chains contributes to inhibition by six class I AADs. Surprisingly, we find that class Ib AADs bind via a strong electrostatic cation-pi interaction, whereas class Ia and Ic AADs rely significantly less on this interaction. Our data shed new light on drug-target interactions underlying the inhibition of cardiac sodium channels by clinically relevant drugs and provide information for the directed design of AADs.",
keywords = "Anti-Arrhythmia Agents, Arrhythmias, Cardiac, Cations, Electrophysiology, Humans, Models, Molecular, Mutagenesis, NAV1.5 Voltage-Gated Sodium Channel, Patch-Clamp Techniques, Phenylalanine, Receptors, Drug, Sodium Channel Blockers, Sodium Channels, Static Electricity",
author = "Pless, {Stephan Alexander} and Galpin, {Jason D} and Adam Frankel and Ahern, {Christopher A}",
year = "2011",
doi = "10.1038/ncomms1351",
language = "English",
volume = "2",
pages = "351",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "nature publishing group",

}

RIS

TY - JOUR

T1 - Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels

AU - Pless, Stephan Alexander

AU - Galpin, Jason D

AU - Frankel, Adam

AU - Ahern, Christopher A

PY - 2011

Y1 - 2011

N2 - Cardiac sodium channels are established therapeutic targets for the management of inherited and acquired arrhythmias by class I anti-arrhythmic drugs (AADs). These drugs share a common target receptor bearing two highly conserved aromatic side chains, and are subdivided by the Vaughan-Williams classification system into classes Ia-c based on their distinct effects on the electrocardiogram. How can these drugs elicit distinct effects on the cardiac action potential by binding to a common receptor? Here we use fluorinated phenylalanine derivatives to test whether the electronegative surface potential of aromatic side chains contributes to inhibition by six class I AADs. Surprisingly, we find that class Ib AADs bind via a strong electrostatic cation-pi interaction, whereas class Ia and Ic AADs rely significantly less on this interaction. Our data shed new light on drug-target interactions underlying the inhibition of cardiac sodium channels by clinically relevant drugs and provide information for the directed design of AADs.

AB - Cardiac sodium channels are established therapeutic targets for the management of inherited and acquired arrhythmias by class I anti-arrhythmic drugs (AADs). These drugs share a common target receptor bearing two highly conserved aromatic side chains, and are subdivided by the Vaughan-Williams classification system into classes Ia-c based on their distinct effects on the electrocardiogram. How can these drugs elicit distinct effects on the cardiac action potential by binding to a common receptor? Here we use fluorinated phenylalanine derivatives to test whether the electronegative surface potential of aromatic side chains contributes to inhibition by six class I AADs. Surprisingly, we find that class Ib AADs bind via a strong electrostatic cation-pi interaction, whereas class Ia and Ic AADs rely significantly less on this interaction. Our data shed new light on drug-target interactions underlying the inhibition of cardiac sodium channels by clinically relevant drugs and provide information for the directed design of AADs.

KW - Anti-Arrhythmia Agents

KW - Arrhythmias, Cardiac

KW - Cations

KW - Electrophysiology

KW - Humans

KW - Models, Molecular

KW - Mutagenesis

KW - NAV1.5 Voltage-Gated Sodium Channel

KW - Patch-Clamp Techniques

KW - Phenylalanine

KW - Receptors, Drug

KW - Sodium Channel Blockers

KW - Sodium Channels

KW - Static Electricity

U2 - 10.1038/ncomms1351

DO - 10.1038/ncomms1351

M3 - Journal article

C2 - 21673672

VL - 2

SP - 351

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

ER -

ID: 122597673