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Biophys J
2015 Mar 24;1086:1435-1447. doi: 10.1016/j.bpj.2015.02.014.
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Sequence of gating charge movement and pore gating in HERG activation and deactivation pathways.
Goodchild SJ
,
Macdonald LC
,
Fedida D
.
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KV11.1 voltage-gated K(+) channels are noted for unusually slow activation, fast inactivation, and slow deactivation kinetics, which tune channel activity to provide vital repolarizing current during later stages of the cardiac action potential. The bulk of charge movement in human ether-a-go-go-related gene (hERG) is slow, as is return of charge upon repolarization, suggesting that the rates of hERG channel opening and, critically, that of deactivation might be determined by slow voltage sensor movement, and also by a mode-shift after activation. To test these ideas, we compared the kinetics and voltage dependence of ionic activation and deactivation with gating charge movement. At 0 mV, gating charge moved ∼threefold faster than ionic current, which suggests the presence of additional slow transitions downstream of charge movement in the physiological activation pathway. A significant voltage sensor mode-shift was apparent by 24 ms at +60 mV in gating currents, and return of charge closely tracked pore closure after pulses of 100 and 300 ms duration. A deletion of the N-terminus PAS domain, mutation R4AR5A or the LQT2-causing mutation R56Q gave faster-deactivating channels that displayed an attenuated mode-shift of charge. This indicates that charge movement is perturbed by N- and C-terminus interactions, and that these domain interactions stabilize the open state and limit the rate of charge return. We conclude that slow on-gating charge movement can only partly account for slow hERG ionic activation, and that the rate of pore closure has a limiting role in the slow return of gating charges.
Arrigoni,
The voltage-sensing domain of a phosphatase gates the pore of a potassium channel.
2013, Pubmed,
Xenbase
Arrigoni,
The voltage-sensing domain of a phosphatase gates the pore of a potassium channel.
2013,
Pubmed
,
Xenbase
Bezanilla,
The voltage sensor in voltage-dependent ion channels.
2000,
Pubmed
Bezanilla,
Distribution and kinetics of membrane dielectric polarization. 1. Long-term inactivation of gating currents.
1982,
Pubmed
Blunck,
Mechanism of electromechanical coupling in voltage-gated potassium channels.
2012,
Pubmed
Chen,
Long QT syndrome-associated mutations in the Per-Arnt-Sim (PAS) domain of HERG potassium channels accelerate channel deactivation.
1999,
Pubmed
,
Xenbase
Chen,
Allosteric effects of permeating cations on gating currents during K+ channel deactivation.
1997,
Pubmed
Cheng,
Voltage-dependent gating of HERG potassium channels.
2012,
Pubmed
Eldstrom,
The voltage-gated channel accessory protein KCNE2: multiple ion channel partners, multiple ways to long QT syndrome.
2011,
Pubmed
Es-Salah-Lamoureux,
Fluorescence-tracking of activation gating in human ERG channels reveals rapid S4 movement and slow pore opening.
2010,
Pubmed
,
Xenbase
Fedida,
Slow gating charge immobilization in the human potassium channel Kv1.5 and its prevention by 4-aminopyridine.
1996,
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
French,
Open-state stabilization in Kv channels: voltage-sensor relaxation and pore propping by a bound ion.
2012,
Pubmed
Gianulis,
Direct interaction of eag domains and cyclic nucleotide-binding homology domains regulate deactivation gating in hERG channels.
2013,
Pubmed
Goodchild,
Contributions of intracellular ions to kv channel voltage sensor dynamics.
2012,
Pubmed
Goodchild,
Gating charge movement precedes ionic current activation in hERG channels.
2014,
Pubmed
Goodchild,
Basis for allosteric open-state stabilization of voltage-gated potassium channels by intracellular cations.
2012,
Pubmed
Gustina,
hERG potassium channel gating is mediated by N- and C-terminal region interactions.
2011,
Pubmed
,
Xenbase
Gustina,
HERG potassium channel regulation by the N-terminal eag domain.
2012,
Pubmed
Gustina,
A recombinant N-terminal domain fully restores deactivation gating in N-truncated and long QT syndrome mutant hERG potassium channels.
2009,
Pubmed
,
Xenbase
Haddad,
Mode shift of the voltage sensors in Shaker K+ channels is caused by energetic coupling to the pore domain.
2011,
Pubmed
,
Xenbase
Haitin,
The structural mechanism of KCNH-channel regulation by the eag domain.
2013,
Pubmed
Hull,
Regional flexibility in the S4-S5 linker regulates hERG channel closed-state stabilization.
2014,
Pubmed
,
Xenbase
January,
Long QT syndrome: cellular basis and arrhythmia mechanism in LQT2.
2000,
Pubmed
Li,
Insight into the molecular interaction between the cyclic nucleotide-binding homology domain and the eag domain of the hERG channel.
2014,
Pubmed
Melishchuk,
Mechanism underlying slow kinetics of the OFF gating current in Shaker potassium channel.
2001,
Pubmed
Mitcheson,
A structural basis for drug-induced long QT syndrome.
2000,
Pubmed
,
Xenbase
Morais Cabral,
Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain.
1998,
Pubmed
,
Xenbase
Muskett,
Mechanistic insight into human ether-à-go-go-related gene (hERG) K+ channel deactivation gating from the solution structure of the EAG domain.
2011,
Pubmed
Ng,
Multiple interactions between cytoplasmic domains regulate slow deactivation of Kv11.1 channels.
2014,
Pubmed
,
Xenbase
Olcese,
Correlation between charge movement and ionic current during slow inactivation in Shaker K+ channels.
1997,
Pubmed
,
Xenbase
Perozo,
Gating currents in Shaker K+ channels. Implications for activation and inactivation models.
1992,
Pubmed
,
Xenbase
Piper,
Voltage sensor movement in the hERG K+ channel.
2005,
Pubmed
Piper,
Gating currents associated with intramembrane charge displacement in HERG potassium channels.
2003,
Pubmed
,
Xenbase
Priest,
S3-S4 linker length modulates the relaxed state of a voltage-gated potassium channel.
2013,
Pubmed
Sanguinetti,
Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel.
1996,
Pubmed
,
Xenbase
Sanguinetti,
A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel.
1995,
Pubmed
,
Xenbase
Sanguinetti,
Delayed rectifier outward K+ current is composed of two currents in guinea pig atrial cells.
1991,
Pubmed
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
Schönherr,
Functional role of the slow activation property of ERG K+ channels.
1999,
Pubmed
,
Xenbase
Smith,
The inward rectification mechanism of the HERG cardiac potassium channel.
1996,
Pubmed
Smith,
Fast and slow voltage sensor movements in HERG potassium channels.
2002,
Pubmed
,
Xenbase
Tan,
Voltage-sensing domain mode shift is coupled to the activation gate by the N-terminal tail of hERG channels.
2012,
Pubmed
,
Xenbase
Thomson,
Concerted all-or-none subunit interactions mediate slow deactivation of human ether-à-go-go-related gene K+ channels.
2014,
Pubmed
,
Xenbase
Thouta,
Proline scan of the HERG channel S6 helix reveals the location of the intracellular pore gate.
2014,
Pubmed
,
Xenbase
Trudeau,
HERG, a human inward rectifier in the voltage-gated potassium channel family.
1995,
Pubmed
Van Slyke,
Mutations within the S4-S5 linker alter voltage sensor constraints in hERG K+ channels.
2010,
Pubmed
,
Xenbase
Varga,
Cations affect the rate of gating charge recovery in wild-type and W434F Shaker channels through a variety of mechanisms.
2002,
Pubmed
,
Xenbase
Villalba-Galea,
S4-based voltage sensors have three major conformations.
2008,
Pubmed
Wang,
Components of gating charge movement and S4 voltage-sensor exposure during activation of hERG channels.
2013,
Pubmed
Wang,
A quantitative analysis of the activation and inactivation kinetics of HERG expressed in Xenopus oocytes.
1997,
Pubmed
,
Xenbase
Warmke,
A family of potassium channel genes related to eag in Drosophila and mammals.
1994,
Pubmed
Wicks,
Sensitivity of HCN channel deactivation to cAMP is amplified by an S4 mutation combined with activation mode shift.
2009,
Pubmed
,
Xenbase
Wymore,
Tissue and species distribution of mRNA for the IKr-like K+ channel, erg.
1997,
Pubmed
,
Xenbase
Yang,
Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes.
2002,
Pubmed
