Voltage-shift of the current activation in HERG S4 mutation (R534C) in LQT2

Nakajima, Tadashi; Furukawa, Tetsushi; Hirano, Yuji; Tanaka, Toshihiro; Sakurada, Harumizu; Takahashi, Tamana; Nagai, Ryozo; Itoh, Toshio; Katayama, Yoshifumi; Nakamura, Yusuke; Hiraoka, Masayasu

doi:10.1016/s0008-6363(99)00195-9

Cited by 48 publications

(30 citation statements)

References 33 publications

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“…In 1999, Nakajima et al [14] reported that position 534 in the S4 region of hERG was involved in voltage-dependent channel activation as a voltage sensor. Kinetic analyses revealed that the R534C mutation shifted the voltage-dependent hERG channel activation to a negative direction, accelerated activation and deactivation time course, and reduced steady-state inactivation.…”

Section: Discussionmentioning

confidence: 99%

Electrophysiological study of V535M hERG mutation of LQT2

Shao

Liu

et al. 2011

J. Huazhong Univ. Sci. Technol. [Med. Sci.]

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This study examined the current changes of human ether-a-go-go-related gene (hERG) mutation derived from a LQT2 Chinese family with a highly penetrating phenotype. Mutation was identified and site-directed mutagenesis was performed to induce the mutation in wild-type (WT) hERG. WT hERG and mutated V535M were cloned and transiently expressed in HEK293 cells. At the 48th and 72nd h after transfection, membrane currents were recorded using whole cell patch-clamp procedures. An A>G transition at 1605 resulting in replacement of V535M was identified. Compared to WT, V535M mutation significantly decreased tail currents of hERG. At test potential of -40 mV after depolarizing at +50 mV, tail current densities were 83.35±7.06 pA/pF in WT and 50.38±7.74 pA/pF in V535M respectively (n=20, P<0.01). Gating kinetics of hERG revealed that V (1/2) of steady-state inactivation shifted to negative potential in the mutant (V (1/2,V535M): -61.81±1.7 mV vs. V (1/2, WT): -43.1±0.71 mV). The time constant of recovery from inactivation was markedly prolonged in the mutant compared to WT among test potentials. V535M hERG mutation demonstrated markedly decreased tail current densities, which suggests that V535M is a new loss-of-function mutation of hERG channel responsible for LQT2.

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Section: Discussionmentioning

confidence: 99%

Electrophysiological study of V535M hERG mutation of LQT2

Shao

Liu

et al. 2011

J. Huazhong Univ. Sci. Technol. [Med. Sci.]

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“…This problem is most clearly exemplified by the study of the R534C mutant Kv11.1 channel. When expressed in Xenopus oocytes, the mutation results in an increased open probability, i.e., a gain of function, yet clinically the mutant causes loss of function (434). Subsequently, it was shown that the R534C mutant when expressed in mammalian cells is retained in the ER, explaining the clinical loss of function (19).…”

Section: Abnormal Gatingmentioning

confidence: 99%

hERG K⁺Channels: Structure, Function, and Clinical Significance

Vandenberg

Perry

Perrin

et al. 2012

Physiological Reviews

621

773

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The human ether-a-go-go related gene (hERG) encodes the pore-forming subunit of the rapid component of the delayed rectifier K(+) channel, Kv11.1, which are expressed in the heart, various brain regions, smooth muscle cells, endocrine cells, and a wide range of tumor cell lines. However, it is the role that Kv11.1 channels play in the heart that has been best characterized, for two main reasons. First, it is the gene product involved in chromosome 7-associated long QT syndrome (LQTS), an inherited disorder associated with a markedly increased risk of ventricular arrhythmias and sudden cardiac death. Second, blockade of Kv11.1, by a wide range of prescription medications, causes drug-induced QT prolongation with an increase in risk of sudden cardiac arrest. In the first part of this review, the properties of Kv11.1 channels, including biogenesis, trafficking, gating, and pharmacology are discussed, while the second part focuses on the pathophysiology of Kv11.1 channels.

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“…Like other members of the K v family of potassium channels, hERG channels are activated by membrane voltage by a mechanism that involves the voltage-sensor domains (8)(9)(10)(11)(12). In hERG channels, voltage-dependent gating is regulated by the large, cytoplasmic N-terminal domain (13)(14)(15)(16)(17).…”

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confidence: 99%

A recombinant N-terminal domain fully restores deactivation gating in N-truncated and long QT syndrome mutant hERG potassium channels

Gustina

Trudeau

2009

Proc. Natl. Acad. Sci. U.S.A.

155

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Human ether á go-go related gene (hERG) potassium channels play a central role in cardiac repolarization where channel closing (deactivation) regulates current density during action potentials. Consequently, mutations in hERG that perturb deactivation are linked to long QT syndrome (LQTS), a catastrophic cardiac arrhythmia. Interactions between an N-terminal domain and the pore-forming ''core'' of the channel were proposed to regulate deactivation, however, despite its central importance the mechanistic basis for deactivation is unclear. Here, to more directly examine the mechanism for regulation of deactivation, we genetically fused N-terminal domains to fluorescent proteins and tested channel function with electrophysiology and protein interactions with Fö rster resonance energy transfer (FRET) spectroscopy. Truncation of hERG N-terminal regions markedly sped deactivation, and here we report that reapplication of gene fragments encoding N-terminal residues 1-135 (the ''eag domain'') was sufficient to restore regulation of deactivation. We show that fluorophore-tagged eag domains and N-truncated channels were in close proximity at the plasma membrane as determined with FRET. The eag domains with Y43A or R56Q (a LQTS locus) mutations showed less regulation of deactivation and less FRET, whereas eag domains restored regulation of deactivation gating to full-length Y43A or R56Q channels and showed FRET. This study demonstrates that direct, noncovalent interactions between the eag domain and the channel core were sufficient to regulate deactivation gating, that an LQTS mutation perturbed physical interactions between the eag domain and the channel, and that small molecules such as the eag domain represent a novel method for restoring function to channels with disease-causing mutations.eag domain ͉ FRET ͉ LQTS H uman ether á go-go related gene (hERG) potassium channels were originally cloned from a human hippocampus library based on homology to mammalian ether á go-go (eag) potassium channels (1). hERG forms the major subunits of the ''rapid component of the cardiac delayed rectifier potassium current'' (I Kr ) in the heart (2, 3). The physiological role of I Kr is to repolarize the late phase of cardiac action potentials (4). The clinical significance of hERG channels and I Kr in the heart is emphasized by mutations in the hERG gene, which are linked to long QT syndrome (LQTS), a cardiac arrhythmia (5). hERG channels are also the targets for inhibitory compounds that cause acquired arrhythmias (6).hERG channels exhibit unusual kinetics that help to specialize them for their role in the heart. With membrane depolarization, hERG channels activate relatively slowly and inactivate rapidly, which limits current amplitude. With subsequent membrane repolarization, hERG channels rapidly recover from inactivation and then very slowly deactivate, which gives rise to a large tail current. The resurgent tail current helps to repolarize the late phase of cardiac action potentials (2-4, 7).The molecular basis for the slow deacti...

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Voltage-shift of the current activation in HERG S4 mutation (R534C) in LQT2

Cited by 48 publications

References 33 publications

Electrophysiological study of V535M hERG mutation of LQT2

Electrophysiological study of V535M hERG mutation of LQT2

hERG K⁺Channels: Structure, Function, and Clinical Significance

A recombinant N-terminal domain fully restores deactivation gating in N-truncated and long QT syndrome mutant hERG potassium channels

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Voltage-shift of the current activation in HERG S4 mutation (R534C) in LQT2

Cited by 48 publications

References 33 publications

Electrophysiological study of V535M hERG mutation of LQT2

Electrophysiological study of V535M hERG mutation of LQT2

hERG K+Channels: Structure, Function, and Clinical Significance

A recombinant N-terminal domain fully restores deactivation gating in N-truncated and long QT syndrome mutant hERG potassium channels

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hERG K⁺Channels: Structure, Function, and Clinical Significance