Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Nature Communications |
Volume | 2 |
Pages (from-to) | 351 |
ISSN | 2041-1723 |
DOIs | |
Publication status | Published - 2011 |
- 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
Research areas
ID: 122597673