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

Stephan A Pless; Jason D Galpin; Adam Frankel; Christopher A Ahern

doi:10.1038/ncomms1351

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

Journal article

Open access

Peer reviewed

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

Stephan A Pless, Jason D Galpin, Adam Frankel and Christopher A Ahern

Nature communications, Vol.2(1), pp.351-351

06/14/2011

DOI: 10.1038/ncomms1351

PMID: 21673672

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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.

Phenylalanine

Anti-Arrhythmia Agents - pharmacology

Cations - metabolism

Humans

Electrophysiology

Models, Molecular

Sodium Channel Blockers - pharmacology

Static Electricity

Receptors, Drug - metabolism

Arrhythmias, Cardiac - drug therapy

Patch-Clamp Techniques

Anti-Arrhythmia Agents - classification

Mutagenesis

Sodium Channels - chemistry

Sodium Channels - metabolism

Sodium Channels - genetics

NAV1.5 Voltage-Gated Sodium Channel

Details

Title: Subtitle: Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels
Creators: Stephan A Pless - Department of Anesthesiology, University of British Columbia, 2350 Health Science Mall, Vancouver, British Columbia, V6T 1Z3 Canada
Jason D Galpin
Adam Frankel
Christopher A Ahern
Resource Type: Journal article
Publication Details: Nature communications, Vol.2(1), pp.351-351
Publisher: England
DOI: 10.1038/ncomms1351
PMID: 21673672
ISSN: 2041-1723
eISSN: 2041-1723
Grant note: 79271 / Canadian Institutes of Health Research 56858 / Canadian Institutes of Health Research
Language: English
Date published: 06/14/2011
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute
Record Identifier: 9984065493102771

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