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
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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