Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Biol Chem
2011 Nov 11;28645:39091-9. doi: 10.1074/jbc.M111.292060.
Show Gene links
Show Anatomy links
Molecular coupling in the human ether-a-go-go-related gene-1 (hERG1) K+ channel inactivation pathway.
Ferrer T
,
Cordero-Morales JF
,
Arias M
,
Ficker E
,
Medovoy D
,
Perozo E
,
Tristani-Firouzi M
.
???displayArticle.abstract???
Emerging evidence suggests that K(+) channel inactivation involves coupling between residues in adjacent regions of the channel. Human ether-a-go-go-related gene-1 (hERG1) K(+) channels undergo a fast inactivation gating process that is crucial for maintaining electrical stability in the heart. The molecular mechanisms that drive inactivation in hERG1 channels are unknown. Using alanine scanning mutagenesis, we show that a pore helix residue (Thr-618) that points toward the S5 segment is critical for normal inactivation gating. Amino acid substitutions at position 618 modulate the free energy of inactivation gating, causing enhanced or reduced inactivation. Mutation of an S5 residue that is predicted to be adjacent to Thr-618 (W568L) abolishes inactivation and alters ion selectivity. The introduction of the Thr-618-equivalent residue in Kv1.5 enhances inactivation. Molecular dynamic simulations of the Kv1.2 tetramer reveal van der Waals coupling between hERG1 618- and 568-equivalent residues and a significant increase in interaction energies when threonine is introduced at the 618-equivalent position. We propose that coupling between the S5 segment and pore helix may participate in the inactivation process in hERG1 channels.
Armstrong,
Inactivation of the sodium channel. II. Gating current experiments.
1977, Pubmed
Armstrong,
Inactivation of the sodium channel. II. Gating current experiments.
1977,
Pubmed
Clarke,
Effect of S5P alpha-helix charge mutants on inactivation of hERG K+ channels.
2006,
Pubmed
,
Xenbase
Cordero-Morales,
Voltage-dependent gating at the KcsA selectivity filter.
2006,
Pubmed
Cordero-Morales,
Molecular determinants of gating at the potassium-channel selectivity filter.
2006,
Pubmed
Cuello,
Structural mechanism of C-type inactivation in K(+) channels.
2010,
Pubmed
Cuello,
Structural basis for the coupling between activation and inactivation gates in K(+) channels.
2010,
Pubmed
Doyle,
The structure of the potassium channel: molecular basis of K+ conduction and selectivity.
1998,
Pubmed
Gajewski,
Biogenesis of the pore architecture of a voltage-gated potassium channel.
2011,
Pubmed
Hoshi,
Two types of inactivation in Shaker K+ channels: effects of alterations in the carboxy-terminal region.
1991,
Pubmed
,
Xenbase
Huffaker,
A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia.
2009,
Pubmed
Humphrey,
VMD: visual molecular dynamics.
1996,
Pubmed
Jiang,
Dynamic conformational changes of extracellular S5-P linkers in the hERG channel.
2005,
Pubmed
Jiang,
Crystal structure and mechanism of a calcium-gated potassium channel.
2002,
Pubmed
Jiang,
X-ray structure of a voltage-dependent K+ channel.
2003,
Pubmed
Jogini,
Dynamics of the Kv1.2 voltage-gated K+ channel in a membrane environment.
2007,
Pubmed
Ju,
The pore domain outer helix contributes to both activation and inactivation of the HERG K+ channel.
2009,
Pubmed
Liu,
Structural and functional role of the extracellular s5-p linker in the HERG potassium channel.
2002,
Pubmed
,
Xenbase
Long,
Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment.
2007,
Pubmed
Panyi,
Cross talk between activation and slow inactivation gates of Shaker potassium channels.
2006,
Pubmed
Perrin,
Drug binding to the inactivated state is necessary but not sufficient for high-affinity binding to human ether-à-go-go-related gene channels.
2008,
Pubmed
Phillips,
Scalable molecular dynamics with NAMD.
2005,
Pubmed
Piper,
Gating currents associated with intramembrane charge displacement in HERG potassium channels.
2003,
Pubmed
,
Xenbase
Piper,
Regional specificity of human ether-a'-go-go-related gene channel activation and inactivation gating.
2005,
Pubmed
Piper,
Cooperative interactions between R531 and acidic residues in the voltage sensing module of hERG1 channels.
2008,
Pubmed
,
Xenbase
Rasmusson,
Inactivation of voltage-gated cardiac K+ channels.
1998,
Pubmed
Sanguinetti,
A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel.
1995,
Pubmed
,
Xenbase
Sanguinetti,
hERG potassium channels and cardiac arrhythmia.
2006,
Pubmed
Schönherr,
Molecular determinants for activation and inactivation of HERG, a human inward rectifier potassium channel.
1996,
Pubmed
,
Xenbase
Smith,
The inward rectification mechanism of the HERG cardiac potassium channel.
1996,
Pubmed
Spector,
Fast inactivation causes rectification of the IKr channel.
1996,
Pubmed
,
Xenbase
Stefani,
Cut-open oocyte voltage-clamp technique.
1998,
Pubmed
,
Xenbase
Stühmer,
Electrophysiological recording from Xenopus oocytes.
1992,
Pubmed
,
Xenbase
Torres,
Structure of the HERG K+ channel S5P extracellular linker: role of an amphipathic alpha-helix in C-type inactivation.
2003,
Pubmed
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
Wang,
Mapping the sequence of conformational changes underlying selectivity filter gating in the K(v)11.1 potassium channel.
2011,
Pubmed
Wang,
HERG K+ channel, a regulator of tumor cell apoptosis and proliferation.
2002,
Pubmed
Warmke,
A family of potassium channel genes related to eag in Drosophila and mammals.
1994,
Pubmed
Yifrach,
Energetics of pore opening in a voltage-gated K(+) channel.
2002,
Pubmed
,
Xenbase
Zhang,
Gating charges in the activation and inactivation processes of the HERG channel.
2004,
Pubmed
,
Xenbase
Zhou,
HERG channel dysfunction in human long QT syndrome. Intracellular transport and functional defects.
1998,
Pubmed
