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 Physiol
2006 Jun 01;573Pt 2:291-304. doi: 10.1113/jphysiol.2006.108332.
Show Gene links
Show Anatomy links
Effect of S5P alpha-helix charge mutants on inactivation of hERG K+ channels.
Clarke CE
,
Hill AP
,
Zhao J
,
Kondo M
,
Subbiah RN
,
Campbell TJ
,
Vandenberg JI
.
???displayArticle.abstract???
The ether-à-go-go (EAG) family of voltage-gated K(+) channels contains three subfamilies, EAG, ether-à-go-go related (ERG) and ether-à-go-go like (ELK). The human ether-à-go-go related gene (hERG) K(+) channel has been of significant interest because loss of function in the hERG channel is associated with a markedly increased risk of cardiac arrhythmias. The hERG channel has unusual kinetics with slow activation and deactivation but very rapid and voltage-dependent inactivation. The outer pore region of the hERG K(+) channel is predicted to be different from that of other members of the voltage-gated K(+) channel family. HERG has a much longer linker between the fifth transmembrane domain (SS) and the pore helix (S5P linker) compared to other families of voltage-gated K(+) channels (43 amino acids compared to 14-23 amino acids). Further, the S5P linker contains an amphipathic alpha-helix that in hERG channels probably interacts with the mouth of the pore to modulate inactivation. The human EAG and rat ELK2 channels (hEAG and rELK2) show reduced or no inactivation in comparison to hERG channels, yet both channels are predicted to contain a similarly long S5P linker to that of hERG. In this study, we have constructed a series of chimaeric channels consisting of the S1-S6 of hERG but with the S5P alpha-helical region of either hEAG or rELK2, and one consisting of the S1-S6 of rELK2 but with the S5P alpha-helical region of hERG to investigate the role of the S5P linker in inactivation. Our studies show that charged residues on the alpha-helix of the S5P linker contribute significantly to the differences in inactivation characteristics of the EAG family channels. Further, individually mutating each of the hydrophilic residues on the S5P alpha-helix of hERG to a charged residue had significant effects on the voltage dependence of inactivation and the two residues with the greatest affect when mutated to a lysine, N588 and Q592, both lie on the same face of the S5P alpha -helix. We suggest that inactivation of hERG involves the interaction of this face of the S5P alpha-helix with a charged residue on the remainder of the outer pore domain of the channel.
Bauer,
Physiology of EAG K+ channels.
2001, Pubmed
Bauer,
Physiology of EAG K+ channels.
2001,
Pubmed
Becchetti,
The functional properties of the human ether-à-go-go-like (HELK2) K+ channel.
2002,
Pubmed
Brugada,
Sudden death associated with short-QT syndrome linked to mutations in HERG.
2004,
Pubmed
Camacho,
Cytoskeletal interactions determine the electrophysiological properties of human EAG potassium channels.
2000,
Pubmed
Clarke,
Mutation of histidine 286 of the human P2X4 purinoceptor removes extracellular pH sensitivity.
2000,
Pubmed
,
Xenbase
Cordeiro,
Modulation of I(Kr) inactivation by mutation N588K in KCNH2: a link to arrhythmogenesis in short QT syndrome.
2005,
Pubmed
Dun,
Allosteric effects of mutations in the extracellular S5-P loop on the gating and ion permeation properties of the hERG potassium channel.
1999,
Pubmed
,
Xenbase
Engeland,
Cloning and functional expression of rat ether-à-go-go-like K+ channel genes.
1998,
Pubmed
Ficker,
Molecular determinants of dofetilide block of HERG K+ channels.
1998,
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
Ganetzky,
The eag family of K+ channels in Drosophila and mammals.
1999,
Pubmed
Hancox,
Time course and voltage dependence of expressed HERG current compared with native "rapid" delayed rectifier K current during the cardiac ventricular action potential.
1998,
Pubmed
Hayashi,
Characterization of a novel missense mutation E637K in the pore-S6 loop of HERG in a patient with long QT syndrome.
2002,
Pubmed
,
Xenbase
Herzberg,
Transfer of rapid inactivation and sensitivity to the class III antiarrhythmic drug E-4031 from HERG to M-eag channels.
1998,
Pubmed
Hoshi,
Two types of inactivation in Shaker K+ channels: effects of alterations in the carboxy-terminal region.
1991,
Pubmed
,
Xenbase
Jiang,
Dynamic conformational changes of extracellular S5-P linkers in the hERG channel.
2005,
Pubmed
Jiang,
Mechanism for the effects of extracellular acidification on HERG-channel function.
1999,
Pubmed
,
Xenbase
Johnson,
Human ether-à-go-go-related gene K+ channel gating probed with extracellular ca2+. Evidence for two distinct voltage sensors.
1999,
Pubmed
Jongbloed,
Novel KCNQ1 and HERG missense mutations in Dutch long-QT families.
1999,
Pubmed
Liu,
Structural and functional role of the extracellular s5-p linker in the HERG potassium channel.
2002,
Pubmed
,
Xenbase
Lu,
Effects of premature stimulation on HERG K(+) channels.
2001,
Pubmed
McPate,
The N588K-HERG K+ channel mutation in the 'short QT syndrome': mechanism of gain-in-function determined at 37 degrees C.
2005,
Pubmed
Meyer,
Characterization of an eag-like potassium channel in human neuroblastoma cells.
1998,
Pubmed
Occhiodoro,
Cloning of a human ether-a-go-go potassium channel expressed in myoblasts at the onset of fusion.
1998,
Pubmed
Piper,
Gating currents associated with intramembrane charge displacement in HERG potassium channels.
2003,
Pubmed
,
Xenbase
Sanguinetti,
A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel.
1995,
Pubmed
,
Xenbase
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
Splawski,
Genomic structure of three long QT syndrome genes: KVLQT1, HERG, and KCNE1.
1998,
Pubmed
Splawski,
Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.
2000,
Pubmed
Subbiah,
Molecular basis of slow activation of the human ether-a-go-go related gene potassium channel.
2004,
Pubmed
,
Xenbase
Torres,
Structure of the HERG K+ channel S5P extracellular linker: role of an amphipathic alpha-helix in C-type inactivation.
2003,
Pubmed
Tseng,
Linkage between 'disruption of inactivation' and 'reduction of K+ selectivity' among hERG mutants in the S5-P linker region.
2006,
Pubmed
,
Xenbase
Vandenberg,
Temperature dependence of human ether-a-go-go-related gene K+ currents.
2006,
Pubmed
Warmke,
A family of potassium channel genes related to eag in Drosophila and mammals.
1994,
Pubmed
Yellen,
An engineered cysteine in the external mouth of a K+ channel allows inactivation to be modulated by metal binding.
1994,
Pubmed
Yellen,
The voltage-gated potassium channels and their relatives.
2002,
Pubmed
Yellen,
The moving parts of voltage-gated ion channels.
1998,
Pubmed
Zhou,
Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature.
1998,
Pubmed
Zou,
A mutation in the pore region of HERG K+ channels expressed in Xenopus oocytes reduces rectification by shifting the voltage dependence of inactivation.
1998,
Pubmed
,
Xenbase
