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Biophys J
2008 May 15;9410:3893-911. doi: 10.1529/biophysj.107.116731.
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Thermodynamic and kinetic properties of amino-terminal and S4-S5 loop HERG channel mutants under steady-state conditions.
Alonso-Ron C
,
de la Peña P
,
Miranda P
,
Domínguez P
,
Barros F
.
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Gating kinetics and underlying thermodynamic properties of human ether-a-go-go-related gene (HERG) K(+) channels expressed in Xenopus oocytes were studied using protocols able to yield true steady-state kinetic parameters. Channel mutants lacking the initial 16 residues of the amino terminus before the conserved eag/PAS region showed significant positive shifts in activation voltage dependence associated with a reduction of z(g) values and a less negative DeltaG(o), indicating a deletion-induced displacement of the equilibrium toward the closed state. Conversely, a negative shift and an increased DeltaG(o), indicative of closed-state destabilization, were observed in channels lacking the amino-terminal proximal domain. Furthermore, accelerated activation and deactivation kinetics were observed in these constructs when differences in driving force were considered, suggesting that the presence of distal and proximal amino-terminal segments contributes in wild-type channels to specific chemical interactions that raise the energy barrier for activation. Steady-state characteristics of some single point mutants in the intracellular loop linking S4 and S5 helices revealed a striking parallelism between the effects of these mutations and those of the amino-terminal modifications. Our data indicate that in addition to the recognized influence of the initial amino-terminus region on HERG deactivation, this cytoplasmic region also affects activation behavior. The data also suggest that not only a slow movement of the voltage sensor itself but also delaying its functional coupling to the activation gate by some cytoplasmic structures possibly acting on the S4-S5 loop may contribute to the atypically slow gating of HERG.
Aydar,
Functional characterization of the C-terminus of the human ether-à-go-go-related gene K(+) channel (HERG).
2001, Pubmed,
Xenbase
Aydar,
Functional characterization of the C-terminus of the human ether-à-go-go-related gene K(+) channel (HERG).
2001,
Pubmed
,
Xenbase
Barros,
Demonstration of an inwardly rectifying K+ current component modulated by thyrotropin-releasing hormone and caffeine in GH3 rat anterior pituitary cells.
1997,
Pubmed
Barros,
The role of the inwardly rectifying K+ current in resting potential and thyrotropin-releasing-hormone-induced changes in cell excitability of GH3 rat anterior pituitary cells.
1994,
Pubmed
Barros,
Modulation of human erg K+ channel gating by activation of a G protein-coupled receptor and protein kinase C.
1998,
Pubmed
,
Xenbase
Bauer,
A functional role of the erg-like inward-rectifying K+ current in prolactin secretion from rat lactotrophs.
1999,
Pubmed
Chen,
Long QT syndrome-associated mutations in the Per-Arnt-Sim (PAS) domain of HERG potassium channels accelerate channel deactivation.
1999,
Pubmed
,
Xenbase
Cherubini,
HERG potassium channels are more frequently expressed in human endometrial cancer as compared to non-cancerous endometrium.
2000,
Pubmed
Chiang,
The long QT syndromes: genetic basis and clinical implications.
2000,
Pubmed
de la Peña,
Cloning and expression of the thyrotropin-releasing hormone receptor from GH3 rat anterior pituitary cells.
1992,
Pubmed
,
Xenbase
Ding,
Effect of S6 tail mutations on charge movement in Shaker potassium channels.
2003,
Pubmed
Emmi,
Do glia have heart? Expression and functional role for ether-a-go-go currents in hippocampal astrocytes.
2000,
Pubmed
Ferrer,
The S4-S5 linker directly couples voltage sensor movement to the activation gate in the human ether-a'-go-go-related gene (hERG) K+ channel.
2006,
Pubmed
,
Xenbase
Finlayson,
Acquired QT interval prolongation and HERG: implications for drug discovery and development.
2004,
Pubmed
Gómez-Varela,
Influence of amino-terminal structures on kinetic transitions between several closed and open states in human erg K+ channels.
2002,
Pubmed
,
Xenbase
Gómez-Varela,
Relevance of the proximal domain in the amino-terminus of HERG channels for regulation by a phospholipase C-coupled hormone receptor.
2003,
Pubmed
,
Xenbase
Ho,
Site-directed mutagenesis by overlap extension using the polymerase chain reaction.
1989,
Pubmed
Keating,
Molecular and cellular mechanisms of cardiac arrhythmias.
2001,
Pubmed
Kupershmidt,
A K+ channel splice variant common in human heart lacks a C-terminal domain required for expression of rapidly activating delayed rectifier current.
1998,
Pubmed
Ledwell,
Mutations in the S4 region isolate the final voltage-dependent cooperative step in potassium channel activation.
1999,
Pubmed
,
Xenbase
Liu,
Negative charges in the transmembrane domains of the HERG K channel are involved in the activation- and deactivation-gating processes.
2003,
Pubmed
,
Xenbase
Miranda,
Specificity of TRH receptor coupling to G-proteins for regulation of ERG K+ channels in GH3 rat anterior pituitary cells.
2005,
Pubmed
Morais Cabral,
Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain.
1998,
Pubmed
,
Xenbase
Overholt,
HERG-Like potassium current regulates the resting membrane potential in glomus cells of the rabbit carotid body.
2000,
Pubmed
Pathak,
The cooperative voltage sensor motion that gates a potassium channel.
2005,
Pubmed
,
Xenbase
Paulussen,
A novel mutation (T65P) in the PAS domain of the human potassium channel HERG results in the long QT syndrome by trafficking deficiency.
2002,
Pubmed
Paulussen,
HERG mutation predicts short QT based on channel kinetics but causes long QT by heterotetrameric trafficking deficiency.
2005,
Pubmed
Piper,
Regional specificity of human ether-a'-go-go-related gene channel activation and inactivation gating.
2005,
Pubmed
Piper,
Gating currents associated with intramembrane charge displacement in HERG potassium channels.
2003,
Pubmed
,
Xenbase
Redfern,
Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development.
2003,
Pubmed
Roden,
Multiple mechanisms in the long-QT syndrome. Current knowledge, gaps, and future directions. The SADS Foundation Task Force on LQTS.
1996,
Pubmed
Rosati,
Glucose- and arginine-induced insulin secretion by human pancreatic beta-cells: the role of HERG K(+) channels in firing and release.
2000,
Pubmed
Saenen,
Modulation of HERG gating by a charge cluster in the N-terminal proximal domain.
2006,
Pubmed
Sanguinetti,
A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel.
1995,
Pubmed
,
Xenbase
Sanguinetti,
Mutations of the S4-S5 linker alter activation properties of HERG potassium channels expressed in Xenopus oocytes.
1999,
Pubmed
,
Xenbase
Schäfer,
The erg-like potassium current in rat lactotrophs.
1999,
Pubmed
Schönherr,
Molecular determinants for activation and inactivation of HERG, a human inward rectifier potassium channel.
1996,
Pubmed
,
Xenbase
Schönherr,
Functional role of the slow activation property of ERG K+ channels.
1999,
Pubmed
,
Xenbase
Schoppa,
Activation of Shaker potassium channels. II. Kinetics of the V2 mutant channel.
1998,
Pubmed
,
Xenbase
Schwartz,
Management of long QT syndrome.
2005,
Pubmed
Smith,
Fast and slow voltage sensor movements in HERG potassium channels.
2002,
Pubmed
,
Xenbase
Smith-Maxwell,
Uncharged S4 residues and cooperativity in voltage-dependent potassium channel activation.
1998,
Pubmed
,
Xenbase
Spector,
Fast inactivation causes rectification of the IKr channel.
1996,
Pubmed
,
Xenbase
Subbiah,
Molecular basis of slow activation of the human ether-a-go-go related gene potassium channel.
2004,
Pubmed
,
Xenbase
Subbiah,
Tryptophan scanning mutagenesis of the HERG K+ channel: the S4 domain is loosely packed and likely to be lipid exposed.
2005,
Pubmed
,
Xenbase
Terlau,
Amino terminal-dependent gating of the potassium channel rat eag is compensated by a mutation in the S4 segment.
1997,
Pubmed
,
Xenbase
Thomas,
Regulation of HERG potassium channel activation by protein kinase C independent of direct phosphorylation of the channel protein.
2003,
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
Viloria,
Differential effects of amino-terminal distal and proximal domains in the regulation of human erg K(+) channel gating.
2000,
Pubmed
,
Xenbase
Viskin,
Long QT syndromes and torsade de pointes.
1999,
Pubmed
Wang,
Dynamic control of deactivation gating by a soluble amino-terminal domain in HERG K(+) channels.
2000,
Pubmed
,
Xenbase
Wang,
Regulation of deactivation by an amino terminal domain in human ether-à-go-go-related gene potassium channels.
1998,
Pubmed
,
Xenbase
Wang,
A quantitative analysis of the activation and inactivation kinetics of HERG expressed in Xenopus oocytes.
1997,
Pubmed
,
Xenbase
Yifrach,
Energetics of pore opening in a voltage-gated K(+) channel.
2002,
Pubmed
,
Xenbase
Zhang,
Interactions between charged residues in the transmembrane segments of the voltage-sensing domain in the hERG channel.
2005,
Pubmed
,
Xenbase
Zhang,
Gating charges in the activation and inactivation processes of the HERG channel.
2004,
Pubmed
,
Xenbase
