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J Physiol
2009 Jun 01;587Pt 11:2555-66. doi: 10.1113/jphysiol.2008.166694.
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The evolutionarily conserved residue A653 plays a key role in HERG channel closing.
Stepanovic SZ
,
Potet F
,
Petersen CI
,
Smith JA
,
Meiler J
,
Balser JR
,
Kupershmidt S
.
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Human ether-a-go-go-related gene (HERG) encodes the rapid, outwardly rectifying K(+) current I(Kr) that is critical for repolarization of the cardiac action potential. Congenital HERG mutations or unintended pharmaceutical block of I(Kr) can lead to life-threatening arrhythmias. Here, we assess the functional role of the alanine at position 653 (HERG-A653) that is highly conserved among evolutionarily divergent K(+) channels. HERG-A653 is close to the 'glycine hinge' implicated in K(+) channel opening, and is flanked by tyrosine 652 and phenylalanine 656, which contribute to the drug binding site. We substituted an array of seven (I, C, S, G, Y, V and T) amino acids at position 653 and expressed individual variants in heterologous systems to assess changes in gating and drug binding. Substitution of A653 resulted in negative shifts of the V(1/2) of activation ranging from -23.6 (A653S) to -62.5 (A653V) compared to -11.2 mV for wild-type (WT). Deactivation was also drastically altered: channels with A653I/C substitutions exhibited delayed deactivation in response to test potentials above the activation threshold, while A653S/G/Y/V/T failed to deactivate under those conditions and required hyperpolarization and prolonged holding potentials at -130 mV. While A653S/G/T/Y variants showed decreased sensitivity to the I(Kr) inhibitor dofetilide, these changes could not be correlated with defects in channel closure. Homology modelling suggests that in the closed state, A653 forms tight contacts with several residues from the neighbouring subunit in the tetramer, playing a key role in S6 helix packing at the narrowest part of the vestibule. Our study suggests that A653 plays an important functional role in the outwardly rectifying gating behaviour of HERG, supporting channel closure at membrane potentials negative to the channel activation threshold.
Adams,
Ionic currents in the human serotonin transporter reveal inconsistencies in the alternating access hypothesis.
2003, Pubmed,
Xenbase
Adams,
Ionic currents in the human serotonin transporter reveal inconsistencies in the alternating access hypothesis.
2003,
Pubmed
,
Xenbase
Armoundas,
Electrical and structural remodeling of the failing ventricle.
2001,
Pubmed
Armstrong,
Voltage-gated K channels.
2003,
Pubmed
Brown,
A highly conserved alanine in the S6 domain of the hERG1 K+ channel is required for normal gating.
2008,
Pubmed
,
Xenbase
Carmeliet,
Voltage- and time-dependent block of the delayed K+ current in cardiac myocytes by dofetilide.
1992,
Pubmed
Chen,
The S4-S5 linker couples voltage sensing and activation of pacemaker channels.
2001,
Pubmed
,
Xenbase
Chen,
Position of aromatic residues in the S6 domain, not inactivation, dictates cisapride sensitivity of HERG and eag potassium channels.
2002,
Pubmed
,
Xenbase
Curran,
A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.
1995,
Pubmed
Decher,
Voltage-dependent gating of hyperpolarization-activated, cyclic nucleotide-gated pacemaker channels: molecular coupling between the S4-S5 and C-linkers.
2004,
Pubmed
,
Xenbase
Ding,
Investigating the putative glycine hinge in Shaker potassium channel.
2005,
Pubmed
,
Xenbase
Doyle,
The structure of the potassium channel: molecular basis of K+ conduction and selectivity.
1998,
Pubmed
Etheridge,
A new oral therapy for long QT syndrome: long-term oral potassium improves repolarization in patients with HERG mutations.
2003,
Pubmed
Fernandez,
Physicochemical features of the HERG channel drug binding site.
2004,
Pubmed
,
Xenbase
Ficker,
Molecular determinants of inactivation and dofetilide block in ether a-go-go (EAG) channels and EAG-related K(+) channels.
2001,
Pubmed
,
Xenbase
Ficker,
Molecular determinants of dofetilide block of HERG K+ channels.
1998,
Pubmed
,
Xenbase
Flynn,
A cysteine scan of the inner vestibule of cyclic nucleotide-gated channels reveals architecture and rearrangement of the pore.
2003,
Pubmed
Herzberg,
Transfer of rapid inactivation and sensitivity to the class III antiarrhythmic drug E-4031 from HERG to M-eag channels.
1998,
Pubmed
Jiang,
The open pore conformation of potassium channels.
2002,
Pubmed
Jiang,
X-ray structure of a voltage-dependent K+ channel.
2003,
Pubmed
Kamiya,
Molecular determinants of HERG channel block.
2006,
Pubmed
,
Xenbase
Kiehn,
Molecular physiology and pharmacology of HERG. Single-channel currents and block by dofetilide.
1996,
Pubmed
,
Xenbase
Kupershmidt,
The IKr drug response is modulated by KCR1 in transfected cardiac and noncardiac cell lines.
2003,
Pubmed
Lees-Miller,
Molecular determinant of high-affinity dofetilide binding to HERG1 expressed in Xenopus oocytes: involvement of S6 sites.
2000,
Pubmed
,
Xenbase
Lippiat,
A residue in the intracellular vestibule of the pore is critical for gating and permeation in Ca2+-activated K+ (BKCa) channels.
2000,
Pubmed
Long,
Voltage sensor of Kv1.2: structural basis of electromechanical coupling.
2005,
Pubmed
Long,
Crystal structure of a mammalian voltage-dependent Shaker family K+ channel.
2005,
Pubmed
Lu,
Ion conduction pore is conserved among potassium channels.
2001,
Pubmed
Lu,
Coupling between voltage sensors and activation gate in voltage-gated K+ channels.
2002,
Pubmed
,
Xenbase
Magidovich,
Conserved gating hinge in ligand- and voltage-dependent K+ channels.
2004,
Pubmed
,
Xenbase
Masetti,
Modeling the hERG potassium channel in a phospholipid bilayer: Molecular dynamics and drug docking studies.
2008,
Pubmed
Mitcheson,
A structural basis for drug-induced long QT syndrome.
2000,
Pubmed
,
Xenbase
Mitcheson,
Structural determinants for high-affinity block of hERG potassium channels.
2005,
Pubmed
Petersen,
In vivo identification of genes that modify ether-a-go-go-related gene activity in Caenorhabditis elegans may also affect human cardiac arrhythmia.
2004,
Pubmed
Pettersen,
UCSF Chimera--a visualization system for exploratory research and analysis.
2004,
Pubmed
Pischalnikova,
The domain and conformational organization in potassium voltage-gated ion channels.
2009,
Pubmed
Roden,
Cardiac ion channels.
2002,
Pubmed
Roden,
Genetics of acquired long QT syndrome.
2005,
Pubmed
Roden,
Inherited long QT syndromes: a paradigm for understanding arrhythmogenesis.
1999,
Pubmed
Rohl,
Modeling structurally variable regions in homologous proteins with rosetta.
2004,
Pubmed
Sanguinetti,
A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel.
1995,
Pubmed
,
Xenbase
Smith,
The inward rectification mechanism of the HERG cardiac potassium channel.
1996,
Pubmed
Smith,
Structural models for the KCNQ1 voltage-gated potassium channel.
2007,
Pubmed
Snyders,
High affinity open channel block by dofetilide of HERG expressed in a human cell line.
1996,
Pubmed
,
Xenbase
Spector,
Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel. Open-channel block by methanesulfonanilides.
1996,
Pubmed
,
Xenbase
Tristani-Firouzi,
Interactions between S4-S5 linker and S6 transmembrane domain modulate gating of HERG K+ channels.
2002,
Pubmed
,
Xenbase
Trudeau,
HERG, a human inward rectifier in the voltage-gated potassium channel family.
1995,
Pubmed
Tseng,
I(Kr): the hERG channel.
2001,
Pubmed
Tsujimae,
Comparison of kinetic properties of quinidine and dofetilide block of HERG channels.
2004,
Pubmed
,
Xenbase
Weinshenker,
Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans.
1999,
Pubmed
Wynia-Smith,
hERG gating microdomains defined by S6 mutagenesis and molecular modeling.
2008,
Pubmed
Zhou,
Chemistry of ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0 A resolution.
2001,
Pubmed
Zou,
Single HERG delayed rectifier K+ channels expressed in Xenopus oocytes.
1997,
Pubmed
,
Xenbase
