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Abstract
The class Ic antiarrhythmic drug flecainide inhibits KCNH2-encoded
“hERG” potassium channels at clinically relevant concentrations. The
aim of this study was to elucidate the underlying molecular basis of
this action. Patch clamp recordings of hERG current (IhERG) were made from hERG expressing cells at 37 °C. Wild-type (WT) IhERG was inhibited with an IC50 of 1.49 μM and this was not significantly altered by reversing the direction of K+ flux or raising external [K+].
The use of charged and uncharged flecainide analogues showed that the
charged form of the drug accesses the channel from the cell interior to
produce block. Promotion of WT IhERG inactivation slowed recovery from inhibition, whilst the N588K and S631A attenuated-inactivation mutants exhibited IC50 values 4–5 fold that of WT IhERG.
The use of pore-helix/selectivity filter (T623A, S624A V625A) and S6
helix (G648A, Y652A, F656A) mutations showed < 10-fold shifts in IC50 for all but V625A and F656A, which respectively exhibited IC50s
27-fold and 142-fold their WT controls. Docking simulations using a
MthK-based homology model suggested an allosteric effect of V625A, since
in low energy conformations flecainide lay too low in the pore to
interact directly with that residue. On the other hand, the molecule
could readily form π–π stacking interactions with aromatic residues and
particularly with F656. We conclude that flecainide accesses the hERG
channel from the cell interior on channel gating, binding low in the
inner cavity, with the S6 F656 residue acting as a principal binding
determinant.
Original language | English |
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Pages (from-to) | 42-53 |
Number of pages | 12 |
Journal | Journal of Molecular and Cellular Cardiology |
Volume | 86 |
Early online date | 6 Jul 2015 |
DOIs | |
Publication status | Published - Sep 2015 |
Keywords
- Flecainide
- hERG
- QT interval
- Repolarization
- Torsades de Pointes
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Dive into the research topics of 'Molecular basis of hERG potassium channel blockade by the class Ic antiarrhythmic flecainide'. Together they form a unique fingerprint.Projects
- 1 Finished
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New pathogenic mechanisms in the long QT syndrome: KCNE1 modulation of hERG.
29/03/15 → 28/09/17
Project: Research
Profiles
-
Dr Christopher E Dempsey
- School of Biochemistry - Senior Lecturer in Biochemistry
- Fundamental Bioscience
Person: Academic , Member
-
Professor Jules C Hancox
- School of Physiology, Pharmacology & Neuroscience - Professor of Cardiac Electrophysiology
Person: Academic