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.
Eur Biophys J
2014 Mar 01;432-3:59-69. doi: 10.1007/s00249-013-0940-y.
Show Gene links
Show Anatomy links
External protons destabilize the activated voltage sensor in hERG channels.
Shi YP
,
Cheng YM
,
Van Slyke AC
,
Claydon TW
.
???displayArticle.abstract???
Extracellular acidosis shifts hERG channel activation to more depolarized potentials and accelerates channel deactivation; however, the mechanisms underlying these effects are unclear. External divalent cations, e.g., Ca(2+) and Cd(2+), mimic these effects and coordinate within a metal ion binding pocket composed of three acidic residues in hERG: D456 and D460 in S2 and D509 in S3. A common mechanism may underlie divalent cation and proton effects on hERG gating. Using two-electrode voltage clamp, we show proton sensitivity of hERG channel activation (pKa = 5.6), but not deactivation, was greatly reduced in the presence of Cd(2+) (0.1 mM), suggesting a common binding site for the Cd(2+) and proton effect on activation and separable effects of protons on activation and deactivation. Mutational analysis confirmed that D509 plays a critical role in the pH dependence of activation, as shown previously, and that cooperative actions involving D456 and D460 are also required. Importantly, neutralization of all three acidic residues abolished the proton-induced shift of activation, suggesting that the metal ion binding pocket alone accounts for the effects of protons on hERG channel activation. Voltage-clamp fluorimetry measurements demonstrated that protons shifted the voltage dependence of S4 movement to more depolarized potentials. The data indicate a site and mechanism of action for protons on hERG activation gating; protonation of D456, D460 and D509 disrupts interactions between these residues and S4 gating charges to destabilize the activated configuration of S4.
Abbruzzese,
Modification of hERG1 channel gating by Cd2+.
2010, Pubmed,
Xenbase
Abbruzzese,
Modification of hERG1 channel gating by Cd2+.
2010,
Pubmed
,
Xenbase
Anumonwo,
Proton and zinc effects on HERG currents.
1999,
Pubmed
,
Xenbase
Bett,
Functionally-distinct proton-binding in HERG suggests the presence of two binding sites.
2003,
Pubmed
,
Xenbase
Bérubé,
Modulation of HERG potassium channel properties by external pH.
1999,
Pubmed
Cha,
Structural implications of fluorescence quenching in the Shaker K+ channel.
1998,
Pubmed
Cheng,
Acidosis inhibits spontaneous activity and membrane currents in myocytes isolated from the rabbit atrioventricular node.
2009,
Pubmed
Claydon,
Voltage clamp fluorimetry studies of mammalian voltage-gated K(+) channel gating.
2007,
Pubmed
DU,
Pharmacological inhibition of the hERG potassium channel is modulated by extracellular but not intracellular acidosis.
2011,
Pubmed
Dong,
Acidification alters antiarrhythmic drug blockade of the ether-a-go-go-related Gene (HERG) Channels.
2004,
Pubmed
,
Xenbase
Du,
Acidosis impairs the protective role of hERG K(+) channels against premature stimulation.
2010,
Pubmed
Es-Salah-Lamoureux,
Fluorescence-tracking of activation gating in human ERG channels reveals rapid S4 movement and slow pore opening.
2010,
Pubmed
,
Xenbase
Fernandez,
Molecular mapping of a site for Cd2+-induced modification of human ether-à-go-go-related gene (hERG) channel activation.
2005,
Pubmed
,
Xenbase
Harris,
Structural basis of perturbed pKa values of catalytic groups in enzyme active sites.
2002,
Pubmed
Ho,
Blockade of HERG channels expressed in Xenopus laevis oocytes by external divalent cations.
1999,
Pubmed
,
Xenbase
Hoshi,
Initial steps in the opening of a Shaker potassium channel.
2012,
Pubmed
Jasti,
Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH.
2007,
Pubmed
Jiang,
Mechanism for the effects of extracellular acidification on HERG-channel function.
1999,
Pubmed
,
Xenbase
Jo,
Blockade of HERG channels expressed in Xenopus oocytes by external H+.
1999,
Pubmed
,
Xenbase
Johnson,
Enhancement of HERG K+ currents by Cd2+ destabilization of the inactivated state.
1999,
Pubmed
Johnson,
Human ether-à-go-go-related gene K+ channel gating probed with extracellular ca2+. Evidence for two distinct voltage sensors.
1999,
Pubmed
Kazmierczak,
External pH modulates EAG superfamily K+ channels through EAG-specific acidic residues in the voltage sensor.
2013,
Pubmed
,
Xenbase
Kehl,
Molecular determinants of the inhibition of human Kv1.5 potassium currents by external protons and Zn(2+).
2002,
Pubmed
Lin,
A mechanism for the potential proarrhythmic effect of acidosis, bradycardia, and hypokalemia on the blockade of human ether-a-go-go-related gene (HERG) channels.
2005,
Pubmed
,
Xenbase
Lin,
The influence of extracellular acidosis on the effect of IKr blockers.
2005,
Pubmed
,
Xenbase
Lin,
Differences between ion binding to eag and HERG voltage sensors contribute to differential regulation of activation and deactivation gating.
2007,
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
Mannuzzu,
Direct physical measure of conformational rearrangement underlying potassium channel gating.
1996,
Pubmed
,
Xenbase
Rulísek,
Coordination geometries of selected transition metal ions (Co2+, Ni2+, Cu2+, Zn2+, Cd2+, and Hg2+) in metalloproteins.
1998,
Pubmed
Sanguinetti,
hERG potassium channels and cardiac arrhythmia.
2006,
Pubmed
Sanguinetti,
Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents.
1990,
Pubmed
Sanguinetti,
A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel.
1995,
Pubmed
,
Xenbase
Silverman,
Mg(2+) modulates voltage-dependent activation in ether-à-go-go potassium channels by binding between transmembrane segments S2 and S3.
2000,
Pubmed
,
Xenbase
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
Terai,
Effects of external acidosis on HERG current expressed in Xenopus oocytes.
2000,
Pubmed
,
Xenbase
Trudeau,
HERG, a human inward rectifier in the voltage-gated potassium channel family.
1995,
Pubmed
Van Slyke,
Proton block of the pore underlies the inhibition of hERG cardiac K+ channels during acidosis.
2012,
Pubmed
,
Xenbase
Van Slyke,
Mutations within the S4-S5 linker alter voltage sensor constraints in hERG K+ channels.
2010,
Pubmed
,
Xenbase
Vandenberg,
hERG K(+) channels: structure, function, and clinical significance.
2012,
Pubmed
Vereecke,
The effect of external pH on the delayed rectifying K+ current in cardiac ventricular myocytes.
2000,
Pubmed
Warmke,
A family of potassium channel genes related to eag in Drosophila and mammals.
1994,
Pubmed
Zhang,
Divalent cations slow activation of EAG family K+ channels through direct binding to S4.
2009,
Pubmed
,
Xenbase
Zhang,
External K(+) relieves the block but not the gating shift caused by Zn(2+) in human Kv1.5 potassium channels.
2001,
Pubmed
Zhou,
Regulation of the voltage-insensitive step of HERG activation by extracellular pH.
2010,
Pubmed
,
Xenbase
